DE60015539T2 - SUBSTITUTED PYRROLIDINES AS INHIBITORS OF CELL ADHESION - Google Patents

Abstract

The invention is directed to physiologically active compounds of formula (I):wherein one of A1, A2 and A3 represents NR2 and the others represent C(R3)(R4); R1 represents R5Z1-Het- or R6N(R7)-C(=O)-NH-Ar2-; Ar1 represents aryldiyl or heteroaryldiyl; L1 represents a -R12-R13- linkage (where R12 is a direct bond or an alkylene chain, an alkenylene chain or an alkynylene chain and R13 is a direct bond, cycloalkylene, heterocycloalkylene, aryldiyl, heteroaryldiyl, -C(=Z3)-NR11-, -NR11-C(=Z3)-, -Z3-, -C(=O)-, -C(=NOR11)-, -NR11-, -NR11-C(=Z3)-NR11-, -SO2-NR11-, -NR -SO2-, -O-C(=O)-, -C(=O)-O-, -NR11-C(=O)-O- or -O-C(=O)-NR11-); and their prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their prodrugs.Such compounds have valuable pharmaceutical properties, in particular the ability to regulate the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (alpha4beta1).

Description

These Invention relates to substituted pyrrolidines, their preparation, pharmaceutical compositions containing these compounds, and their pharmaceutical use in the treatment of disease states which can be modulated by the inhibition of cell adhesion.

Cell adhesion is a process in which cells associate with one another Goal or migrate within the extra-cellular matrix Arrange. Many of the Cell Cell and Cell Extracellular Matrix Interactions are by protein ligands (for example, fibronectin, VCAM-1 and vitronectin) and their integrin receptors [eg, α5β1 (VLA-5), α4β1 (VLA-4) and αVβ3]. Recent studies have shown that these interactions account for a significant proportion in many physiological (eg embryonic development and wound healing) and pathological conditions (e.g., tumor cell invasion and metastasis, inflammation, Atherosclerosis and autoimmune disease).

A a wide variety of proteins serve as ligands for integrin receptors. In general, the proteins recognized by integrins fall within one of the three classes: extracellular matrix proteins, plasma proteins and Cell surface proteins. Extracellular Matrix proteins such as collagen fibronectin, fibrinogen, laminin, thrombospondin and vitronectin bind to a variety of integrins. Many of the adhesive Proteins also circulate in the plasma and bind to activated blood cells. additional Components in the plasma that are ligands for integrins include fibrinogen and factor X Cell-bound complement C3bi and various Trans-membrane proteins, such as Ig-type cell adhesion molecule (ICAM-1,2,3) and vascular cell adhesion molecule (VCAM-1), the members which are Ig superfamily also serve as cell surface ligands for some Integrins.

integrins are heterodimeric cell surface receptors, consisting of two subunits called α and β. There are at least fifteen different α subunits (α1-α9, α-L, α-M, α-X, α-IIb, α-V and α-E) and at least seven different β- (β1-β7) subunits. The integrin family can be divided into two classes based on the β-subunits, be associated with one or more α-subunits can. The most widely used integrins belong to the β1 class, also known as the very late Antigens (VLA). The second class of integrins are leukocyte-specific Receptors and consist of one of three α-subunits (α-L, α-M or α-X) complexed with the β2 protein. The cytoadhesins make α-IIbβ3 and α-Vβ3 the third class of integrins.

The The present invention relates primarily to agents which control the interaction of ligand VCAM-1 with its integrin receptor α4β1 (VLA-4) numerous hematopoietic Cells and established cell lines, including hematopoietic Precursors, peripheral and cytotoxic T lymphocytes, B lymphocytes, Monocytes, thymocytes and eosinophils.

The Integrin α4β1 mediates both cell-cell and cell-matrix interactions. α4β1-expressing Cells bind to the carboxy-terminated cell binding domain (CS-1) of the extracellular Matrix protein fibronectins, to the cytokine inducible endothelial Cell surface protein VCAM-1 and each other to promote homotypic aggregation. The Expression of VCAM-1 by endothelial cells is by pro inflammatory Cytokines, such as INF-γ, TNF-α, IL-1β and IL-4, upregulated.

Regulation of α4β1-mediated cell adhesion is important in numerous physiological processes, including T cell proliferation, B cell localization at germinal centers, and adhesion of activated T cells and eosinophils to endothelial cells. Evidence for the involvement of VLA-4 / VCAM-1 interaction in various disease processes, such as melanoma cell division in metastasis, T-cell infiltration of synovial membranes in rheumatoid arthritis, autoimmune diabetes, colitis, and leukocyte penetration of the blood-brain barrier in experimental autoimmune encephalomyelitis Atherosclerosis, peripheral vascular disease, cardiovascular disease and multiple sclerosis were studied by examining the role of the peptide CS-1 (the variable region of fibronectin to which α4β1 binds via the sequence Leu-Asp-Val) and antibodies responsible for VLA -4 or VCAM-1 are specific in various in vitro and in vivo inflammatory experimental models. For example, in a streptococcal cell wall-induced, experimental model of arthritis in rats, intravenous administration of CS-1 at the onset of arthritis suppresses both acute and chronic inflammation (SM Wahl et al., J. Clin. Invest., 1994, 94; Pages 655-662). In the oxazalone-sensitized model of inflammation (contact hypersensitivity reaction) in mice, intravenous administration of anti-α4 specific monoclonal antibodies significantly (50-60% reduction in ear swelling) inhibited the efferent response (PL Chisholm et al. J. Immunol., 1993, 23, pages 682-688). In a sheep model of allergic bronchoconstriction, HP1 / 2, an anti-α4 monoclonal antibody given intravenously or by aerosol, blocked the late response and development of airway hyperreactivity (WM Abraham et al., J. Clin Invest, 1994, 93; Pages 776-787).

EP-A-0842945 discloses the use of N-substituted pyrrolidone, imidazolidinone, Oxazolidinone and thiazolidinone derivatives as inhibitors of leukocyte adhesion and as VLA-4 antagonists.

We have now found a new group of substituted pyrrolidines, the valuable pharmaceutical properties, especially the ability for regulating the interaction of VCAM-1 and fibronectin with the integrin VLA-4 (α4β1).

worin:
einer von A¹, A² und A³ NR² wiedergibt und die anderen C(R³)(R⁴) wiedergeben;
R¹ R⁵Z¹-Het- oder R⁶N(R⁷)-C(=O)-NH-Ar²- wiedergibt;
R²-C(=O)-R⁸, -C(=O)-OR^8a oder R^8b wiedergibt;
R³ und R⁴ jeweils Wasserstoff oder R⁸ wiedergeben;
R⁵ Aryl; Heteroaryl; Alkyl, Alkenyl oder Alkinyl, jeweils gegebenenfalls substituiert mit R⁹, -Z²R¹⁰, -Z³H, -C(=O)-R¹⁰, -NR¹¹-C(=Z³)-R¹¹, -NR¹¹-C(=O)-OR¹⁰, -NR¹¹-SO₂-R¹⁰, -SO₂-NY¹Y², -NY¹Y² oder -C(=Z³)-NY¹Y²; oder Cycloalkyl, oder Heterocycloalkyl, jeweils gegebenenfalls substituiert mit R¹⁰, -Z²R¹⁰, -Z³H, -C(=O)-R¹⁰, -NR¹¹-C(=Z³)-R¹⁰, -NR¹¹-C(=O)-OR¹⁰, -NR¹¹-SO₂-R¹⁰, -SO₂-NY¹Y², -NY¹Y² oder -C(=Z³)-NY¹Y², wiedergibt;
R⁶ Wasserstoff oder Niederalkyl wiedergibt und R⁷ Aryl, Arylalkyl, Heteroaryl oder Heteroarylalkyl wiedergibt; oder
R⁶ und R⁷ zusammen mit dem Stickstoffatom, an das sie gebunden sind, ein cyclisches Amin bilden;
R⁸ Alkyl, Aryl, Arylalkyl, Cycloalkyl, Cycloalkylalkyl, Heteroaryl, Heteroarylalkyl, Heterocycloalkyl oder Heterocyc loalkylalkyl oder Alkyl, substituiert mit einer sauren funktionellen Gruppe oder einem entsprechenden geschützten Derivat, oder mit -Z³H, -Z²R¹⁰, -C(=O)-NY¹Y² oder -NY¹Y², wiedergibt;
R^8a Alkyl, Aryl, Arylalkyl, Heteroaryl oder Heteroarylalkyl wiedergibt;
R^8b Alkyl, Aryl, Arylalkyl, Heteroaryl, Heteroarylalkyl oder Alkyl, substituiert mit einer sauren funktionellen Gruppe oder einem entsprechenden geschützten Derivat, wiedergibt;
R⁹ Aryl, Cycloalkyl, Cycloalkenyl, Heteroaryl oder Heterocycloalkyl wiedergibt;
R¹⁰ Alkyl, Alkenyl, Alkinyl, Aryl, Arylalkyl, Arylalkenyl, Arylalkinyl, Cycloalkyl, Cycloalkylalkyl, Cycloalkenyl, Cycloalkenylalkyl, Heteroaryl, Heteroarylalkyl, Heteroarylalkenyl, Heteroarylalkinyl, Heterocycloalkyl oder Heterocycloalkylalkyl wiedergibt;
R¹¹ Wasserstoff oder Niederalkyl wiedergibt;
R¹² eine direkte Bindung oder eine Alkylenkette, eine Alkenylenkette, oder eine Alkinylenkette darstellt;
R¹³ eine direkte Bindung, Cycloalkylen, Heterocycloalkylen; Aryldiyl, Heteroaryldiyl, -C(=Z³)-NR¹¹-, -NR¹¹-C(=Z³)-, -Z³-, -C(=O)-, -C(=NOR¹¹)-, -NR¹¹-, -NR¹¹-C(=Z³)-NR¹¹-, SO₂-NR¹¹-, -NR¹¹-SO₂-, -O-C(=O)-, -C(=O)-O-, -NR¹¹-C(=O)-O- oder -O-C(=O)-NR¹¹- wiedergibt;
Ar¹ Aryldiyl oder Heteroaryldiyl wiedergibt;
Ar² Aryldiyl oder Heteroaryldiyl wiedergibt;
Het ein gesättigtes, teilweise gesättigtes oder vollständig ungesättigtes 8- bis 10-gliedriges bicyclisches Ringsystem, das mindestens ein Heteroatom, ausgewählt aus O, S oder N, gegebenenfalls substituiert mit einem oder mehreren Arylgruppensubstituenten, wiedergibt;
L¹ eine -R¹²-R¹³-Bindung wiedergibt;
Y Carboxy oder ein saures Bioisosteres, ausgewählt aus der Gruppe, bestehend aus -C(=O)-NHOH, -C(=O)-CH₂OH, -C(=O)-CH₂SH, -C(=O)-NH-CN, Sulfo, Phosphono, Alkylsulfonylcarbamoyl, Tetrazolyl, Arylsulfonylcarbamoyl, Heteroarylsulfonylcarba moyl, N-Methoxycarbamoyl, 3-Hydroxy-3-cyclobuten-1,2-dion, 3,5-Dioxo-1,2,4-oxadiazolidinyl, 3-Hydroxyisoxazolyl und 3-Hydroxy-1-methylpyrazolyl, darstellt;
Y¹ und Y² unabhängig Wasserstoff, Alkenyl, Alkyl, Aryl, Arylalkyl, Cycloalkyl, Heteroaryl oder Heteroarylalkyl darstellen; oder die Gruppe -NY¹Y² ein cyclisches Amin bilden kann;
Z¹ NH wiedergibt;
Z² O oder S(O)_n darstellt;
Z³ O oder S darstellt;
n Null oder eine ganze Zahl 1 oder 2 ist;
(jedoch ausschließlich Verbindungen, in denen ein Sauerstoff-, Stickstoff- oder Schwefelatom direkt an die Kohlenstoff-Kohlenstoff-Mehrfachbindung eines Alkenyl- oder Alkinylrestes gebunden ist);
und deren Esterprodrugs und pharmazeutisch verträgliche Salze und Solvate (z.B. Hydrate) von solchen Verbindungen und deren Esterprodrugs.Thus, in one aspect, the present invention relates to compounds of the general formula (I):

wherein:
one of A ¹ , A ² and A ^{3 represents} NR ² and the other C (R ³ ) represent (R ⁴ );
R ¹ R ^{5 is} Z ¹ -Het or R ⁶ N (R ⁷ ) -C (= O) -NH-Ar ² -;
R ^{2 represents} -C (= O) -R ⁸ , -C (= O) -OR ^8a or R ^8b ;
R ³ and R ⁴ each represent hydrogen or R ⁸ ;
R ⁵ aryl; heteroaryl; Alkyl, alkenyl or alkynyl, each optionally substituted with R ⁹ , -Z ² R ¹⁰ , -Z ³ H, -C (= O) -R ¹⁰ , -NR ¹¹ -C (= Z ³ ) -R ¹¹ , -NR ¹¹ -C (= O) -OR ¹⁰ , -NR ¹¹ -SO ₂ -R ¹⁰ , -SO ₂ -NY ¹ Y ² , -NY ¹ Y ² or -C (= Z ³ ) -NY ¹ Y ² ; or cycloalkyl, or heterocycloalkyl, each optionally substituted with R ¹⁰ , -Z ² R ¹⁰ , -Z ³ H, -C (= O) -R ¹⁰ , -NR ¹¹ -C (= Z ³ ) -R ¹⁰ , -NR ¹¹ -C (= O) -OR ¹⁰ , -NR ¹¹ -SO ₂ -R ¹⁰ , -SO ₂ -NY ¹ Y ² , -NY ¹ Y ² or -C (= Z ³ ) -NY ¹ Y ² ;
R ^{6 represents} hydrogen or lower alkyl and R ^{7 represents} aryl, arylalkyl, heteroaryl or heteroarylalkyl; or
R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a cyclic amine;
R ^{8 is} alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl or alkyl substituted with an acidic functional group or a corresponding protected derivative, or with -Z ³ H, -Z ² R ¹⁰ , -C (= O) -NY ¹ Y ² or -NY ¹ Y ² , represents;
R ^{8a represents} alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl;
R ^{8b represents} alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkyl substituted with an acidic functional group or a corresponding protected derivative;
R ^{9 represents} aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycloalkyl;
R ^{10 represents} alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl;
R ^{11 represents} hydrogen or lower alkyl;
R ^{12 represents} a direct bond or an alkylene chain, an alkenylene chain, or an alkynylene chain;
R ^{13 is} a direct bond, cycloalkylene, heterocycloalkylene; Aryldiyl, heteroaryldiyl, -C (= Z ³ ) -NR ¹¹ -, -NR ¹¹ -C (= Z ³ ) -, -Z ³ -, -C (= O) -, -C (= NOR ¹¹ ) -, -NR ¹¹ -, -NR ¹¹ -C (= Z ³ ) -NR ¹¹ -, SO ₂ -NR ¹¹ -, -NR ¹¹ -SO ₂ -, -OC (= O) -, -C (= O) - O-, -NR ¹¹ -C (= O) -O- or -OC (= O) -NR ¹¹ -;
Ar ^{1 represents} aryldiyl or heteroaryldiyl;
Ar ^{2 represents} aryldiyl or heteroaryldiyl;
Het is a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system which represents at least one heteroatom selected from O, S or N, optionally substituted with one or more aryl group substituents;
L ^{1 represents} an -R ¹² -R ¹³ bond;
Y carboxy or an acidic bioisosteres selected from the group consisting of -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ SH, -C (= O ) -NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl , 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl;
Y ¹ and Y ^{2 are} independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY ¹ Y ² may form a cyclic amine;
Z ^{1 represents} NH;
Z ^{2 represents} O or S (O) _n ;
Z ^{3 represents} O or S;
n is zero or an integer 1 or 2;
(but only compounds in which an oxygen, nitrogen or sulfur atom is bonded directly to the carbon-carbon multiple bond of an alkenyl or alkynyl radical);
and their ester prodrugs and pharmaceutically acceptable salts and solvates (eg hydrates) of such compounds and their ester prodrugs.

In As used herein, the term "compounds of the invention" and equivalents Terms that compounds of general formula (I), as herein described above, the term being the ester prodrugs, the pharmaceutically acceptable Salts and the solvates, for example hydrates, if the context it allows, includes. In similar Way, the reference to intermediates means whether they claim themselves or not, that their salts, solvates, if the context it is thus allowed to include. For the sake of clarity, individual cases are when the context allows it, sometimes shown in the text, however are these cases only explanatory and not provided, other cases ruled out if the context allows it.

"Patient" closes both Human as well as other mammals one.

"Acid bioisoster" means a group that has chemical and physical similarities that produce largely similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemistry, 1986, 21, page 283 "Bioisosterism In Drug Design", Yun, Hwahak Sekye, 1993, 33, pages 576-579 "Application of Bioisosterism to New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38 "Bioisosteric Replacement and Development of Lead Compounds in Drug Design"; Graham, Theochem, 1995; 343, pages 105-109 "Theoretical Studies Applied To Drug Design: Ab initio Electronic Distributions In Bioisosteres"). Examples of suitable acidic bioisosteres are: -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ SH, -C (= O) -NH-CN, sulfo, Phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N -methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl.

"Acid functional Group "means a group with an acidic hydrogen in it. The "accordingly protected Derivatives "are those where the acidic hydrogen atom is replaced by a suitable protecting group has been. For suitable protecting groups see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry ", John Wiley and Sons, 1991. Exemplary Acid Functional Protecting Groups shut down Carboxyl (and acidic bioisosteres), hydroxy, mercapto and imidazole one. Exemplary protected Derivatives include esters of carboxy groups, ethers of hydroxy groups, thioethers of mercapto groups and N-benzyl derivatives of imidazoles.

"Acyl" means a group H-CO- or alkyl-CO-, wherein the alkyl group is as hereinbefore is described.

"Acylamino" is a group Acyl-NH-, wherein acyl is as defined herein.

"Alkenyl" means an aliphatic one Hydrocarbon group containing a carbon-carbon double bond contains and which may be straight or branched, with about 2 to about 15 Carbon atoms in the chain. Preferred alkenyl groups have From 2 to about 12 carbon atoms in the chain and more preferably about 2 to about 4 carbon atoms in the chain. "Branched" as used herein and throughout the text means that one or more lower alkyl groups, such as methyl, Ethyl or propyl attached to a linear chain; here one linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain that are straight or branched Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl and decenyl.

"Alkenylene" means an aliphatic divalent radical derived from a straight or branched C _2-6 alkenyl group. Exemplary alkenylene radicals include vinylene and propylene.

"Alkoxy" means a group Alkyl-O- wherein the alkyl group is as described herein. Exemplary alkoxy groups shut down Methoxy, ethoxy, n-propoxy, i -propoxy, n-butoxy and heptoxy.

"Alkoxycarbonyl" means a group Alkyl-O-CO- wherein the alkyl group is as described herein. exemplary Close alkoxycarbonyl groups Methoxy and ethoxycarbonyl.

"Alkyl" means, if so not stated otherwise, an aliphatic hydrocarbon group, which may be straight or branched, having from about 1 to about 15 carbon atoms in the chain, optionally substituted with alkoxy or with one or more halogen atoms. Individual alkyl groups have 1 to about 6 carbon atoms. "Lower alkyl" is a group or a part of a lower alkoxy group, and means, if not Otherwise indicated, an aliphatic hydrocarbon group, the may be straight or branched, having from about 1 to about 4 carbon atoms in the chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, heptyl, octyl, nonyl, decyl and dodecyl.

"Alkylene" means an aliphatic divalent radical derived from a straight or branched C _1-6 alkyl group. Exemplary alkylene radicals include methylene, ethylene and trimethylene.

"Alkylenedioxy" means a group -O-alkyl-O-, wherein the alkyl group is as defined above. exemplary Close alkylenedioxy groups Methylenedioxy and ethylenedioxy.

"Alkylsulfinyl" means a group of alkyl-SO- wherein the alkyl group is as described above. Preferred alkylsulfinyl groups are those wherein the alkyl group is C _1-4 alkyl.

"Alkylsulfonyl" means a group of alkyl-SO ₂ -, wherein the alkyl group is as described above. Preferred alkylsulfonyl groups are those wherein the alkyl group is C _1-4 alkyl.

"Alkylsulfonylcarbamoyl" means a group of alkyl-SO ₂ -NH-C (= O) -, wherein the alkyl group is as described above. Preferred alkylsulfonylcarbamoyl groups are those wherein the alkyl group is C _1-4 alkyl.

"Alkylthio" means a group Alkyl-S- wherein the alkyl group is as described above. Exemplary alkylthio groups include methylthio, ethylthio, Isopropylthio and heptylthio.

"Alkynyl" means an aliphatic one Hydrocarbon group that has a carbon-carbon triple bond contains and which may be straight or branched with about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Exemplary alkynyl groups include ethynyl, Propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl and n-pentynyl one.

"Alkynylene" means an aliphatic divalent radical derived from a C _2-6 alkynyl group. Exemplary alkynylene radicals include ethynylene and propynylene.

"Aroyl" means a group Aryl-CO- wherein the aryl group is as described herein. Exemplary aroyl groups shut down Benzoyl and 1- and 2-naphthoyl.

"Aroylamino" is a group Aroyl-NH- wherein aroyl is as defined above.

"Aryl", as a group or part of a group, means: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) an optionally substituted, partially saturated, multicyclic aromatic, carbocyclic moiety wherein an aryl and a cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure, such as a tetrahydronaphthyl, indenyl or indanyl ring. Aryl groups may be substituted with one or more aryl group substituents which may be the same or different, with "aryl group substituent" being, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, Aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, cyano, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, hydroxy, nitro, trifluoromethyl, Y ¹ Y ² N-, Y ¹ Y ² NCO-, Y ¹ Y ² NSO ₂ -, Y ¹ Y ² NC _2-6 -alkylene-Z- {wherein Z is O, NR ¹¹ or S (O) _n }, alkyl (C = O) -Y ¹ N-, alkylSO ₂ -Y ¹ N - or alkyl optionally substituted with aryl, heteroaryl, hydroxy or Y ¹ Y ² N-. When R ^{5 represents} an optionally substituted aryl group, it may particularly represent optionally substituted phenyl.

"Arylalkenyl" means an aryl-alkenyl group, wherein the aryl and alkenyl units are as described above are.

"Arylalkyl" means an aryl-alkyl group wherein the aryl and alkyl moieties are as described above are written. Preferred arylalkyl groups contain a C _1-4 alkyl moiety. Exemplary arylalkyl groups include benzyl, 2-phenethyl and naphthalene methyl.

"Arylalkyloxy" means a group Arylalkyl-O-, wherein the arylalkyl groups are as described above are. Exemplary arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy one.

"Arylalkyloxycarbonyl" means a group Arylalkyl-O-CO-, wherein the arylalkyl groups are as described above. A Exemplary arylalkyloxycarbonyl group is benzyloxycarbonyl.

"Arylalkylthio" means a group Arylalkyl-S- wherein the arylalkyl group is as described above is. An exemplary arylalkylthio group is benzylthio.

"Arylalkynyl" means an aryl-alkynyl group, wherein the aryl and alkynyl are as described above. exemplary Close arylalkynyl groups Phenylethynyl and 3-phenylbut-2-ynyl one.

"Aryldiyl" means an optional one substituted divalent radical derived from an aryl group is. Exemplary aryldiyl groups include optionally substituted ones Phenylene, naphthylene and indanylene. Suitable substituents shut down one or more "aryl group substituents" as above defined, in particular halogen, methyl or methoxy, a.

"Aryloxy" means a group Aryl-O-, wherein the aryl group is as described above. exemplary Close aryloxy groups optionally substituted phenoxy and naphthoxy.

"Aryloxycarbonyl" means a group Aryl-O-CO-, wherein the aryl group is as described above. Exemplary aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl one.

"Arylsulfinyl" means a group Aryl-SO-, wherein the aryl group is as described above.

"Arylsulfonyl" means a group of aryl-SO ₂ -, wherein the aryl group is as described above.

"Arylsulfonylcarbamoyl" means a group of aryl-SO ₂ -NH-C (= O) -, wherein the aryl group is as described above.

"Arylthio" means a group Aryl-S-, wherein the aryl group is as described above. exemplary Close arylthio groups Phenylthio and naphthylthio.

"Azaheteroaryl" means an aromatic carbocyclic moiety of from about 5 to about 10 ring members, wherein one of the ring links represents nitrogen and the others Ring members made of carbon, oxygen, sulfur or nitrogen selected are. examples for Close the azaheteroaryl groups Pyridyl, pyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, imidazolyl, Oxazolyl and benzimidazolyl.

"Azaheteroaryldiyl" means a bivalent one Residue derived from a heteroaryl group.

"Cyclic amine" means a 3- to 8-membered monocyclic cycloalkyl ring system in which one of the ring carbon atoms is replaced by nitrogen, and (i) optionally substituted with one or more substituents selected from alkoxy, carboxamido, carboxy, hydroxy, Oxo (or a 5-, 6- or 7-membered cyclic acetal derivative thereof) or R ⁸ ; (ii) may also contain another heteroatom selected from O, S, SO ₂ or NY ³ (wherein Y ^{3 is} hydrogen, alkyl, aryl, arylalkyl, -C (= O) -R ¹⁴ , -C (= O) - OR ¹⁴ or -SO ₂ R ¹⁴ , and R ^{14 represents} alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl); and (iii) may be fused to further aryl (e.g., phenyl), heteroaryl (e.g., pyridyl), heterocycloalkyl, or cycloalkyl rings to form a bicyclic or tricyclic ring system. Exemplary cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline and pyrindoline, tetrahydroquinolinyl and the like groups. When the group R ^{6 represents} N (R ⁷ ) - a cyclic amine, it may in particular represent indolinyl or tetrahydroquinolinyl.

"Cycloalkenyl" means a non-aromatic, monocyclic or multicyclic ring system containing at least one Carbon-carbon double bond and at least about 3 to contains about 10 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, Cyclohexenyl or cycloheptenyl.

"Cycloalkenylalkyl" means a cycloalkenyl-alkyl group wherein the Cycloalkenyl and alkyl moieties as described above.

"Cycloalkylalkenyl" means a cycloalkyl-alkenyl group wherein the Cycloalkyl and alkenyl units as described above.

"Cycloalkyl" means a saturated, monocyclic or bicyclic ring system having from about 3 to about 10 carbon atoms optionally substituted with oxo. Exemplary monocyclic cycloalkyl rings include C _3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl.

"Cycloalkylalkyl" means a cycloalkyl-alkyl group, wherein the cycloalkyl and alkyl moieties are as described above are. Exemplary monocyclic cycloalkylalkyl groups include cyclopropylmethyl, Cyclopentylmethyl, cyclohexylmethyl and cycloheptylmethyl.

"Cycloalkylalkenyl" means a cycloalkyl-alkenyl group wherein the Cycloalkyl and alkenyl units as described above.

"Cycloalkylalkynyl" means a cycloalkyl-alkynyl group wherein the Cycloalkyl and Alkinyl units as described above.

"Cycloalkylene" means a bivalent one Residue derived from a cycloalkyl group. exemplary Close cycloalkylene radicals Cyclopentylene and cyclohexylene.

"Halo" or "halogen" means fluoro, Chlorine, bromine or iodine. Preference is given to fluorine or chlorine.

"Heteroaroyl" means a group Heteroaryl-C (= O) -, wherein the heteroaryl group is as described above is. Exemplary groups include pyridylcarbonyl.

"Heteroaroylamino" means a group Heteroaroyl-NH-, wherein the heteroaryl moiety is as described above.

"Heteroaryl", as a group or part of a group means: (i) an optionally substituted aromatic monocyclic or multicyclic organic moiety of about 5 to about 10 ring members, wherein one or more of the ring members Represents element (s) other than carbon, For example, nitrogen, oxygen or sulfur (examples of such Close groups Benzimidazolyl, benzthiazolyl, furyl, imidazolyl, indolyl, Indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, Oxazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, Pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, Thienyl and triazolyl groups, optionally substituted with one or more aryl group substituents as defined above); (ii) an optionally substituted, partially saturated, multicyclic heterocarbocyclic moiety wherein one heteroaryl and one cycloalkyl or cycloalkenyl group are fused together to form a cyclic structure (examples of such groups include pyrindanyl groups one). Optional substituents include one or more, such as above defined "aryl group substituents".

"Heteroarylalkenyl" means a heteroaryl-alkenyl group in which the Heteroaryl and alkenyl radicals are as described above.

"Heteroarylalkynyl" means a heteroaryl-alkynyl group in which the Heteroaryl and alkynyl radicals as described above.

"Heteroarylalkyl" means a heteroaryl-alkyl group wherein the heteroaryl and alkyl moieties are as described above. Preferred heteroarylalkyl groups contain a C _1-4 alkyl moiety. Exemplary heteroarylalkyl groups include pyridylmethyl.

"Heteroarylalkyloxy" means a group Heteroarylalkyl-O- wherein the heteroarylalkyl group is as above is described. Exemplary heteroaryloxy groups optionally include substituted pyridylmethoxy.

"Heteroaryldiyl" means a bivalent one Residue derived from a heteroaryl group.

"Heteroaryloxy" means a group Heteroaryl-O-, wherein the heteroaryl group is as described above is. Exemplary heteroaryloxy groups include optionally substituted ones Pyridyloxy.

"Heteroarylsulfonylcarbamoyl" means a group of heteroaryl-SO ₂ -NH-C (= O) -, wherein the heteroaryl group is as described above.

"Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 7 ring members containing one or more heteroatoms selected from O, S or NY ³ and optionally substituted with oxo; (ii) a partially saturated multicyclic heterocarbocyclic moiety wherein an aryl (or heteroaryl ring) is each optionally substituted with one or more "aryl group substituents" and a heterocycloalkyl group is fused together to form a cyclic structure (examples of such groups include chromanyl) , Dihydrobenzofuranyl, indolinyl and pyrindolinyl groups).

"Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl group wherein the heterocycloalkyl and alkyl moieties as described above are.

"Heterocycloalkylene" means a bivalent one Residue derived from a heterocycloalkyl group.

"Hydroxyalkyl" means a group HO-alkyl- wherein alkyl is as defined above Preferred hydroxyalkyl groups include C _1-4 alkyl, for example hydroxymethyl and 2-hydroxyethyl.

"Phenylene" means an optional one substituted divalent radical derived from a phenyl group is. Suitable substituents include one or more "aryl group substituents" as above defined, in particular halogen, methyl or methoxy, a.

"Prodrug" means a compound in vivo by metabolic means (for example by hydrolysis) into a compound of formula (I), including N-oxides thereof convertible is. For example, an ester of a compound of formula (I), which contains a hydroxy group, be convertible by hydrolysis in vivo to the parent molecule. alternative may be an ester of a compound of formula (I) having a carboxy group contains be convertible by hydrolysis in vivo to the parent molecule.

suitable Esters of the compounds of the formula (I) which contain a hydroxyl group, are, for example, acetates, citrates, lactates, tartrates, malonates, Oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene-bis-β-hydroxynaphthoates, Gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, Benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates.

suitable Esters of the compounds of the formula (I) which contain a carboxy group, For example, those described by F.J. Leinweber, Drug Metab. Res., 1987, 18, 379.

A particularly useful class of esters of compounds of the formula (I) containing a hydroxy group may be acid units be formed, selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, p 2503-2507 be, and close substituted (aminomethyl) benzoates, for example dialkylaminomethylbenzoates, in which the two alkyl groups may be bonded together and / or by an oxygen atom or by an optionally substituted Nitrogen atom, for example an alkylated nitrogen atom, interrupted could be, in particular (morpholinomethyl) benzoates, for example 3- or 4- (morpholinomethyl) benzoates, and (4-alkylpiperazin-1-yl) benzoates, for example 3- or 4- (4-alkylpiperazin-1-yl) benzoates.

When the compound of the present invention contains a carboxy group or a sufficiently acidic bioisoster, base addition salts can be formed and are simply a more suitable form of application. In practice, the use of the salt form inherently amounts to the use of the free acid form. The bases which can be used to prepare the base addition salts preferably include those which, when combined with the free acid, produce pharmaceutically acceptable salts; ie, salts whose cations are non-toxic to the patient in pharmaceutical doses of the salts such that the beneficial inhibitory effects inherent in the free base are not mitigated by side effects attributable to the cations. Pharmaceutically acceptable salts, including those derived from alkali and alkaline earth metal salts, include within the scope of the invention those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylene diamine , N-Me thylglucamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, tetramethylammonium hydroxide and the like.

Some the compounds of the invention are basic, and such compounds are in free base form or in the form of a pharmaceutically acceptable acid addition salt thereof.

Acid addition salts are another suitable form of application; and in practice amounts to the use of salt form inherent on the use of the free base form. The acids used to make the Acid addition salts can be used shut down preferably those which, when combined with the free base, pharmaceutically acceptable Produce salts; i.e. Salts, their anions for the patient in pharmaceutical Doses of the salts are not toxic so that the beneficial inhibitor effects, those inherent in the free base, not by side effects, that attributable to the anions are attenuated. Although pharmaceutical compatible Salts of the base compounds are preferred are all acid addition salts usable as sources of the free base form, even if the respective Salt itself is desired only as an intermediate, such as, for example, if the salt is only for Purposes of cleaning and identification is formed, or if it as an intermediate in the manufacture of a pharmaceutical compatible salt is used by ion exchange method. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids are derived and close Hydrohalides, for example hydrochlorides and hydrobromides, Sulfates, phosphates, nitrates, sulfamates, acetates, citrates, lactates, Tartrates, malonates, oxalates, salicylates, propionates, succinates, Fumarates, maleates, methylene-bis-β-hydroxynaphthoates, Gentisates, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, Benzenesulfonates, p-toluenesulfonates, cyclohexylsulfamates and quinates one.

Even useful as active ingredients are the salts of the compounds of the invention also for the purpose of cleaning compounds for example by use the solubility differences between the salts and the parent compounds, by-products and / or Starting materials by techniques well known to those skilled in the art are, useful.

darstellt, worin Ring

einen 5- oder 6-gliedrigen Heteroarylring darstellt und Ring

einen 5- oder 6-gliedrigen Heteroaryl- oder einen Benzolring darstellt, jeder Ring gegebenenfalls mit einem oder mehreren „Arylgruppensubstituenten", wie vorstehend definiert, ist, und die zwei Ringe miteinander durch eine Kohlenstoff-Kohlenstoff-Bindung oder eine Kohlenstoff-Stickstoff-Bindung verbunden sind.With reference to formula (I) above, the groupings below are particular and preferred groupings:
R ¹ may in particular represent a group R ⁵ Z ¹ -Het-, wherein R ^{5 is} optionally substituted aryl (especially optionally substituted phenyl), optionally substituted heteroaryl, arylalkyl (for example benzyl and phenethyl) or cycloalkyl (for example cyclohexyl), Z ¹ NH and Het is an 8- to 10-membered bicyclic system

represents, wherein ring

represents a 5- or 6-membered heteroaryl ring and ring

represents a 5- or 6-membered heteroaryl or a benzene ring, each ring is optionally substituted with one or more "aryl group substituents" as defined above, and the two rings are linked together by a carbon-carbon bond or a carbon-nitrogen bond are connected.

kann insbesondere einen 5-gliedrigen Heteroarylring (insbesondere einen 5-gliedrigen Azaheteroarylring), gegebenenfalls substituiert mit einem oder mehreren „Arylgruppensubstituenten", wie vorstehend definiert, wiedergeben.ring

may in particular be a 5-membered heteroaryl ring (especially a 5-membered azaheteroaryl ring) optionally substituted with one or more "aryl group substituents" as defined above, such as dergeben.

kann insbesondere einen Benzolring, gegebenenfalls substituiert mit einem oder mehreren „Arylgruppensubstituenten", wie vorstehend definiert, wiedergeben.ring

may in particular represent a benzene ring optionally substituted with one or more "aryl group substituents" as defined above.

kann insbesondere ein 9-gliedriges bicyclisches Ringsystem wiedergeben, worin Ringe

und

wie gerade vorstehend definiert sind, und die zwei Ringe miteinander durch Kohlenstoffatombindungen verbunden sind.

ist vorzugsweise gegebenenfalls substituiertes Benzoxazolyl oder gegebenenfalls substituiertes Benzimidazolyl, jeweils (insbesondere Ring

) gegebenenfalls substituiert mit einem oder mehreren „Arylgruppensubstituenten", wie vorstehend definiert [Beispiele für einige Arylgruppensubstituenten schließen Niederalkyl (beispielsweise Methyl), Niederalkoxy (beispielsweise Methoxy), Amino, Halogen, Hydroxy, Niederalkylthio, Niederalkylsulfinyl, Niederalkylsulfonyl, Nitro oder Trifluormethyl ein].

In particular, it may represent a 9-membered bicyclic ring system wherein rings

and

as just defined above, and the two rings are bonded together by carbon atoms bonds.

is preferably optionally substituted benzoxazolyl or optionally substituted benzimidazolyl, respectively (especially ring

Examples of some aryl group substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), amino, halo, hydroxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl].

R ¹ can also represent in particular a group R ⁶ N (R ⁷ ) -C (OO) -NH-Ar ² -, in which R ^{6 is} C _1-4 -alkyl (for example methyl or ethyl, in particular methyl), R ⁷ Aryl (especially optionally substituted phenyl wherein the optional substituent is an "aryl group substituent" as defined above) and Ar ² (i) is optionally substituted phenylene such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, in particular methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl), or (ii) optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optionally present substituents C _1-4 -alkyl and the like and C _1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl substituted at the 4- or 6-position with a methyl or methoxy group. Ar ² is preferably optionally substituted phenylene (for example, p-phenylene), especially when the substituent is C _1-4 alkyl or C _1-4 alkoxy.

R ¹ can also represent in particular a group R ⁶ N (R ⁷ ) -C (OO) -NH-Ar ² -, in which R ^{6 is} C _1-4 -alkyl (for example methyl or ethyl, in particular methyl), R ⁷ Arylalkyl, in particular aryl-CH ₂ - or aryl-CH (CH ₃ ) -, preferably optionally substituted benzyl or optionally substituted 1-phenylethyl, when the optionally present substituent is an "aryl group substituent", as vorste and Ar ² (i) is optionally substituted phenylene such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 Alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl), or (ii) optionally substituted Azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, where the optionally present substituents C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, on the 4- or 6-position with a methyl or methoxy group is substituted.

In particular, R ¹ may also represent a group R ⁶ N (R ⁷ ) -C (= O) -NH-Ar ² - where R ^{6 is} N (R ⁷ ) - a bicyclic amine containing 9-10 atoms, especially indolinyl or tetrahydroquinolinyl, and Ar ² (i) optionally substituted phenylene such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 Alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl), or (ii) optionally substituted Azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, when the optionally present substituents C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl, at the 4- or 6-position with a methyl or metho xygruppe is substituted, represents.

R ¹ can also in particular represent a group R ⁶ N (R ⁷ ) -C (OO) -NH-Ar ² -, in which R ^{6 is} hydrogen, R ^{7 is} (i) aryl, in particular optionally substituted aryl, wherein the optionally present Substituent is an "aryl group substituent" as defined above, or (ii) optionally substituted pyridyl, especially optionally substituted 2-pyridyl (preferred optional substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy ) and Ar ² (i) is optionally substituted phenylene such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl), or (ii) optionally substituted Azaheteroaryldiyl such as optionally substituted pyridinediyl, preferably a p-pyridinediyl where the optional substituents are C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy, more preferably a pyridine-2,5-diyl which is attached to the 4 or 6-position substituted with a methyl or methoxy group. R ⁷ is in particular phenyl or ortho-substituted phenyl [preferred substituents include C _1-4 alkoxy, for example methoxy], or in particular C _1-4 alkyl (for example methyl)]. Ar ² is preferably optionally substituted phenylene (for example, p-phenylene), especially where the substituent is C _1-4 alkyl or C _1-4 alkoxy.

L ¹ may in particular represent a bond -R ¹² -R ¹³ -, wherein R ^{12 represents} a straight or branched C _1-6 alkylene chain, in particular a straight or branched C _1-4 alkylene chain (for example methylene), and R ¹³ -C (= Z ³ ) -NR ¹¹ , preferably -C (= O) -NR ¹¹ , in particular wherein R ^{11 is} hydrogen or lower alkyl (for example methyl).

Ar ¹ can in particular optionally substituted aryldiyl, in particular optionally substituted m- or p-phenylene, especially optionally substituted p-phenylene, play. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Ar ¹ may also represent in particular optionally substituted azaheteroaryldiyl, in particular optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Ar ¹ is preferably unsubstituted p-phenylene.

One of A ¹ , A ² and A ³ may in particular represent NR ² (especially where R ^{2 is} -C (= O) -R ⁸ or arylC _1-4 alkyl, for example benzyl) and the other CH ₂ play. R ⁸ may preferably represent C _1-4 alkyl or phenyl.

Y may in particular represent carboxy.

It is understandable, that this invention all suitable combinations of the particular and preferred herein Groupings covers.

As used above and throughout the description of the invention, the following terms, unless otherwise indicated, be understood to have the following meanings:

worin A¹, A², A³, R¹², Ar¹ und Y wie in einem relevanten vorangehenden Anspruch definiert sind; R¹⁵ Wasserstoff, Halogen, Niederalkyl oder Niederalkoxy darstellt, X¹ CR¹⁶ (worin R¹⁶ Wasserstoff, Niederalkyl oder Niederalkoxy darstellt) wiedergibt; X² und X³ unabhängig N oder CR¹⁷ (worin R¹⁷ Wasserstoff, Amino, Halogen, Hydroxy, Niederalkyl, Niederalkoxy, Niederalkylthio, Niederalkylsulfinyl, Niederalkylsulfonyl, Nitro oder Trifluormethyl darstellt) wiedergeben und die R¹² enthaltende Gruppe an den Ring in 3- oder 4-Position gebunden ist und deren Esterprodrugs und pharmazeutisch verträgliche Salze und Solvate von Verbindungen der Formel (Ia) und deren Esterprodrugs.A particular group of compounds according to the invention are compounds of the formula (Ia):

wherein A ¹ , A ² , A ³ , R ¹² , Ar ¹ and Y are as defined in a relevant preceding claim; R ^{15 represents} hydrogen, halogen, lower alkyl or lower alkoxy, X ^{1 represents} CR ¹⁶ (wherein R ^{16 represents} hydrogen, lower alkyl or lower alkoxy); X ² and X ^{3 are} independently N or CR ¹⁷ (wherein R ^{17 is} hydrogen, amino, halogen, hydroxy, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, nitro or trifluoromethyl) and the R ¹² containing group is attached to the ring in 3 or 4-position and their ester prodrugs and pharmaceutically acceptable salts and solvates of compounds of formula (Ia) and their ester prodrugs.

Compounds of formula (Ia) wherein R ^{15 represents} hydrogen are preferred.

Compounds of formula (Ia) wherein X ^{1 represents} CR ¹⁶ wherein R ^{16 represents} C _1-4 alkyl (for example methyl) are preferred.

Compounds of formula (Ia) in which X ^{2 represents} CR ¹⁷ , in particular wherein R ^{17 represents} C _1-4 alkoxy (for example methoxy), are also preferred.

Compounds of formula (Ia) wherein X ^{3 represents} CH are also preferred.

Compounds of the formula (Ia) in which R ^{12 represents} a straight or branched C _1-6 alkylene chain, in particular a straight C _1-4 alkylene chain, especially methylene, are preferred.

Compounds of the formula (Ia) in which Ar ^{1 represents} an optionally substituted aryldiyl, in particular optionally substituted m- or p-phenylene, especially optionally substituted p-phenylene, are preferred. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Ia) wherein Ar ^{1 represents} optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, are also preferred. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Ia) wherein Ar ^{1 represents} unsubstituted p-phenylene are particularly preferred.

Compounds of formula (Ia) wherein one of A ¹ , A ² and A ^{3 represents} NR ² [especially when R ^{2 is} -C (= O) -R ⁸ or arylC _1-4 alkyl] and the others Reproduce CH ₂ are preferred.

links of formula (Ia) wherein Y represents carboxy are preferred.

The group containing R ¹² is preferably attached to the ring 4 position.

A preferred group of compounds are compounds of formula (Ia) wherein: R ^{15 is} hydrogen, X ^{1 is} CR ¹⁶ (especially when R ^{16 is} C _1-4 alkyl, for example methyl); X ^{2 is} CR ¹⁷ (especially when R ^{17 is} C _1-4 alkoxy, for example methoxy); X ^{3 represents} CH; R ¹² a ge Rade is C _1-4 alkylene chain (especially methylene); Ar ^{1 represents} an optionally substituted phenylene (for example, methyl- or methoxy-substituted p-phenylene, or especially unsubstituted p-phenylene); one of A ¹ , A ² and A ³ NR ² (wherein R ^{2 is} -C (= O) -R ⁸ when R ^{8 is} C _1-4 alkyl or phenyl or R ^{2 is} arylC _1-4 alkyl , for example, benzyl) and the other CH _{2 represent} ; Y represents carboxy and the R ¹² -containing group is attached to the ring 4-position, and their ester prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of such compounds and their ester prodrugs.

worin R¹¹, R¹², Ar¹, Ar², A¹, A², A³ und Y wie hierin vorstehend definiert sind, und deren Esterprodrugs und pharmazeutisch verträgliche Salze und Solvate (beispielsweise Hydrate) von Verbindungen der Formel (Ib) und deren Esterprodrugs.Another preferred group of compounds according to the invention are compounds of the formula (Ib):

wherein R ¹¹ , R ¹² , Ar ¹ , Ar ² , A ¹ , A ² , A ³ and Y are as hereinbefore defined, and their ester prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of compounds of formula (Ib) and their ester prodrugs.

Compounds of formula (Ib) wherein Ar ^{2 is} optionally substituted aryldiyl such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 alkyl , C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl) are preferred.

Compounds of formula (Ib) wherein Ar ^{2 represents} optionally substituted azaheteroaryldiyl such as optionally substituted pyridinediyl, preferably p-pyridinediyl, when the optional substituents are C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy , more preferably a pyridine-2,5-diyl substituted at the 4- or 6-position with a methyl or methoxy group are also preferred.

Compounds of the formula (Ib) in which R ^{12 represents} a straight or branched C _1-6 -alkylene chain, in particular a straight or branched C _1-4 -alkylene chain, especially methylene, are preferred.

Compounds of formula (Ib) wherein R ^{11 represents} hydrogen are preferred.

Compounds of formula (Ib) wherein R ^{11 represents} lower alkyl (for example methyl) are also preferred.

Compounds of the formula (Ib) in which Ar ^{1 represents} an optionally substituted aryldiyl, in particular optionally substituted m- or p-phenylene, especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar ¹ include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Ib) wherein Ar ^{1 represents} optionally substituted azaheteroaryldiyl, especially optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, are also preferred. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Ib) wherein one of A ¹ , A ² and A ^{3 represents} NR ² (especially wherein R ^{2 is} -C (= O) -R ⁸ or arylC _1-4 alkyl) and the others Reproduce CH ₂ are preferred.

links of the formula (Ib) wherein Y represents carboxy are preferred.

A preferred group of compounds according to the invention are compounds of the formula (Ib) in which:
Ar ² p-phenylene or substituted p-phenylene (especially 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p- phenylene) or p-pyridinediyl or substituted p-pyridinediyl [especially 4- (or 6) -methoyl (or -methoxy) -p-pyridine-2,5-diyl]; R ^{12 represents} a straight or branched C _1-4 alkylene chain (especially methylene); R ^{11 is} hydrogen or lower alkyl (e.g., methyl); Ar ^{1 represents} an optionally substituted aryldiyl [especially p-phenylene, and methyl (or methoxy) -substituted p-phenylene]; one of A ¹ , A ² and A ³ NR ² (wherein R ^{2 is} -C (= O) -R ⁸ wherein R ^{8 is} C _1-4 alkyl or phenyl, or R ^{2 is} arylC _1-4 alkyl, for example benzyl) and the other CH _{2 represent} ; Y represents carboxy, and their ester prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of such compounds and their ester prodrugs.

worin R¹¹, R¹², Ar¹, Ar², A¹, A², A³ und Y wie hierin vorstehend definiert sind; R⁶ Niederalkyl darstellt, R¹⁸ Wasserstoff oder Methyl darstellt, Ar³ Aryl darstellt und m null oder 1 ist, und deren Esterprodrugs und pharmazeutisch verträgliche Salze und Solvate (beispielsweise Hydrate) von Verbindungen der Formel (Ic) und deren Esterprodrugs.A particularly preferred group of compounds according to the invention are compounds of the formula (Ic):

wherein R ¹¹ , R ¹² , Ar ¹ , Ar ² , A ¹ , A ² , A ³ and Y are as defined hereinbefore; R ⁶ is lower alkyl, R ^{18 is} hydrogen or methyl, Ar ^{3 is} aryl and m is zero or 1, and their ester prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of compounds of formula (Ic) and their ester prodrugs.

Compounds of formula (Ic) wherein Ar ^{3 represents} phenyl optionally substituted with an "aryl group substituent" as defined above are preferred.

Compounds of formula (Ic) wherein R ^{6 represents} C _1-4 alkyl, especially methyl or ethyl, are preferred. Compounds of formula (Ic) wherein Ar ^{2 is} optionally substituted aryldiyl such as optionally substituted m- or p-phenylene, preferably optionally substituted p-phenylene, more preferably a 3-substituted p-phenylene (preferred optional substituents include C _1-4 alkyl , C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl and C _1-4 alkylsulfonyl, especially methyl, methoxy, methylthio, methylsulfinyl and methylsulfonyl) are preferred.

Compounds of formula (Ic) wherein Ar ^{2 represents} optionally substituted azaheteroaryldiyl, such as optionally substituted pyridinediyl, preferably a p-pyridinediyl, wherein the optional substituents are C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy , more preferably a pyridine-2,5-diyl substituted at the 4- or 6-position with a methyl or methoxy group are also preferred.

Compounds of formula (Ic) wherein R ^{12 represents} a straight or branched C _1-6 alkylene chain, especially a straight or branched C _1-4 alkylene chain, especially methylene, are preferred.

Compounds of formula (Ic) wherein R ^{11 represents} hydrogen are preferred.

Compounds of formula (Ic) wherein R ^{11 represents} lower alkyl (for example methyl) are also preferred.

Compounds of the formula (Ic) in which Ar ^{1 represents} an optionally substituted aryldiyl, in particular optionally substituted m- or p-phenylene, especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar ¹ include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of the formula (Ic) in which Ar ^{1 represents} optionally substituted azaheteroaryldiyl, in particular optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, are also preferred. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Ic) wherein one of A ¹ , A ² and A ^{3 represents} NR ² (especially wherein R ^{2 is} -C (= O) -R ⁸ or arylC _1-4 alkyl), and the other CH ₂ are preferred.

links of formula (Ic) wherein Y represents carboxy are preferred.

A preferred group of compounds according to the invention are compounds of the formula (Ic) in which:
Ar ^{3 represents} phenyl; R ^{18 is} hydrogen or methyl; m is zero or one; R ^{6 is} C _1-4 alkyl (especially methyl or ethyl); Ar ² p-phenylene or optionally substituted p-phenylene (especially 3-methyl-p-phenylene, 3-methoxy-p-phenylene, 3-methylthio-p-phenylene, 3-methylsulfinyl-p-phenylene and 3-methylsulfonyl-p -phenylene), or p-pyridinediyl or substituted p-pyridinediyl [especially 4- (or 6 -) - methyl (or - methoxy -) - p -pyridine-2,5-diyl]; R ^{12 represents} a straight or branched C _1-4 alkylene chain (especially methylene); R ^{11 is} hydrogen or lower alkyl (e.g., methyl); Ar ^{1 represents} an optionally substituted phenylene [especially p-phenylene and methyl (or methoxy) -substituted p-phenylene]; one of A ¹ , A ² and A ³ NR ² (wherein R ^{2 is} -C (= O) -R ⁸ wherein R ^{8 is} C _1-4 alkyl or phenyl, or R ^{2 is} arylC _1-4 alkyl, for example benzyl) and the other CH _{2 represent} ; Y represents carboxy; and the corresponding N-oxides and their ester prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of such compounds and their N-oxides and ester prodrugs.

worin R⁵, R¹², Ar¹, A¹, A², A³ und Y wie vorstehend definiert sind; X NR oder 0 (wo-rin R H oder Niederalkyl darstellt) darstellt; R¹⁹ Wasserstoff, C_1-4-Alkyl oder C_1-4-Alkoxy darstellt und deren Esterprodrugs; und pharmazeutisch verträg liche Salze und Solvate (z.B. Hydrate) von Verbindungen der Formel (Id) und deren Esterprodrugs.Another particular group of compounds according to the invention are the compounds of the formula (Id):

wherein R ⁵ , R ¹² , Ar ¹ , A ¹ , A ² , A ³ and Y are as defined above; X represents NR or O (where r is R or lower alkyl); R ^{19 is} hydrogen, C _1-4 -alkyl or C _1-4 -alkoxy and their ester prodrugs; and pharmaceutically acceptable salts and solvates (eg hydrates) of compounds of formula (Id) and their ester prodrugs.

Compounds of the formula (Id) in which R ^{5 represents} optionally substituted aryl, in particular optionally substituted phenyl, are preferred. Preferred optional substituents include lower alkyl (e.g. methyl), lower alkoxy (e.g. methoxy), halo (e.g. fluoro) and Y ¹ Y ² N- (e.g. dimethylamino). In particular, R ^{5 represents} ortho-tolyl.

Compounds of the formula (Id) in which R ^{12 represents} a straight or branched C _1-6 -alkylene chain, in particular a straight C _1-4 -alkylene chain, especially methylene, are preferred.

Compounds of the formula (Id) in which Ar ^{1 represents} an optionally substituted aryldiyl, in particular optionally substituted m- or p-phenylene, especially optionally substituted p-phenylene, are preferred. Preferred substituents for Ar ¹ include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of formula (Id) in which Ar ^{1 represents} optionally substituted azaheteroaryldiyl, in particular optionally substituted pyridinediyl, especially optionally substituted p-pyridinediyl, are also preferred. Preferred substituents include C _1-4 alkyl and C _1-4 alkoxy, especially methyl and methoxy.

Compounds of the formula (Id) in which Ar ^{1 represents} unsubstituted p-phenylene are particularly be vorzugt.

Compounds of formula (Id) in which one of A ¹ , A ² and A ^{3 represents} NR ² (in particular wherein R ^{2 is} -C (= O) -R ⁸ or arylC _1-4 alkyl), and the other CH ₂ are preferred.

links of formula (Id) wherein Y represents carboxy are preferred.

A preferred group of compounds of the invention are compounds of formula (Id) wherein: R ^{5 is} optionally substituted phenyl, especially ortho-tolyl; X represents O; R ^{12 represents} a straight C _1-4 alkylene chain (especially methylene); Ar ^{1 represents} an optionally substituted phenylene (for example, methyl- or methoxy-substituted p-phenylene or especially unsubstituted p-phenylene); one of A ¹ , A ² and A ³ NR ² (wherein R ^{2 is} -C (= O) -R ⁸ wherein R ^{8 is} C _1-4 alkyl or phenyl or R ^{2 is} arylC _1-4 alkyl represents, for example, benzyl) and the other CH _{2 represent} , Y represents carboxy, and the group containing R ¹² is bonded to the benzoxazole ring 6 position and the corresponding N-oxides and their prodrugs and pharmaceutically acceptable salts and solvates ( for example, hydrates) of such compounds and their N-oxides and ester prodrugs.

Particular compounds of the invention are selected from the following:
1-benzyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1- (3-carboxy-propionyl) -4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3- carboxylic acid;
1- (5-methyl-isoxazole-3-carbonyl) -4- (4- {2- [4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) pyrrolidine 3-carboxylic acid;
1-acetyl-4- [4- (methyl - {[4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4- (methyl - {[4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4- (methyl - {[4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -amino) -phenyl] -1- (thiophen-2-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4- (methyl - {[4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -amino) -phenyl] -1- (pyridin-4-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4- (methyl - {[4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -amino) -phenyl] -1- (morpholin-4-yl-acetyl) - pyrrolidine-3-carboxylic acid;
1- (5-methyl-isoxazole-3-carbonyl) -4- {4- [methyl - ({4- [3-methyl-3- (2-methyl-hexa-1,3,5-trienyl) -ureido ] -phenyl} -acetyl) -amino] -phenyl} -pyrrolidine-3-carboxylic acid;
1-acetyl-4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) -phenyl] -1- (thiophen-2-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) phenyl] -1- (pyridin-4-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) -phenyl] -1- (morpholin-4-yl-acetyl) - pyrrolidine-3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetylamino) -phenyl] -1- (5-methyl-isoxazole-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -pyrroli din-3-carboxylic acid;
1-benzoyl-4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -pyrrolidin-3- carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -1- (thiophen-2-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -1- (pyridin-4-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -1- (morpholin-4-yl -acetyl) -pyrrolidine-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -phenyl} -acetyl) -methyl-amino] -phenyl} -1- (5-methyl-isoxazol -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) pyrrolidine 3-carboxylic acid;
4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) pyrrolidine 3-carboxylic acid;
4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) - pyrrolidine-3-carboxylic acid;
4- (4- {2- [3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -1- (5-methyl-isoxazole-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3- carboxylic acid;
1-benzoyl-4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3- carboxylic acid;
4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl -acetyl) -pyrrolidine-3-carboxylic acid;
4- [4 - ({[3-methoxy-4- (3-methyl-3-o-tolyl-ureido) -phenyl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-isoxazol -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) -phenyl] -pyrrolidine-3- carboxylic acid;
1-benzoyl-4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) -phenyl] -pyrrolidine-3- carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) -phenyl] -1- (thiophen-2-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) phenyl] -1- (pyridin-4-carbonyl ) -pyrrolidin-3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) -phenyl] -1- (morpholin-4-yl -acetyl) -pyrrolidine-3-carboxylic acid;
4- [4- (2- {4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetylamino) -phenyl] -1- (5-methyl-isoxazol -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} - pyrrolidine-3-carboxylic acid;
1-benzoyl-4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} - pyrrolidine-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} -1- (thiophen -2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} -1- (pyridin -4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} -1- (morpholin -4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- {4 - [({4 - [(2,3-dihydro-indol-1-carbonyl) -amino] -3-methoxy-phenyl} -acetyl) -methyl-amino] -phenyl} -1- (5 -methyl-isoxazol-3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1- (thiophene-2-carbonyl) -4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1- (pyridine-4-carbonyl) -4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1- (morpholin-4-yl-acetyl) -4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- {4- [2- (2-o-tolylamino-benzoxazol-6-yl) acetylamino] phenyl} pyrrolidine 3-carboxylic acid;
1-Acetyl-4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (pyridine-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- (4- {methyl - [(2-o-tolylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl ) -pyrrolidin-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (2-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) -pyrroli din-3-carboxylic acid;
4- [4 - ({[2- (2-ethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (2-ethyl-phemylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (2-chloro-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3- carboxylic acid;
4- (4- {2- [2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3 carbonyl) pyrrolidine-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) - pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2,6-dimethyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro isoxazole-3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3- carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (3-cyano-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- [4 - ({[2- (3-methoxy-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -1- (thiophene-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -1- (pyridin-4-carbonyl) -pyrrolidine-3-carboxylic acid;
1- (morpholin-4-yl-acetyl) -4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- {4- [2- (2-phenylamino-benzoxazol-6-yl) -acetylamino] -phenyl} -pyrrolidine-3- carboxylic acid;
1-Acetyl-4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (thiophen-2-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (pyridine-4-carbonyl) -pyrrolidine-3-carboxylic acid;
4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) acetyl] amino} phenyl) -1- (morpholin-4-yl-acetyl) -pyrrolidine-3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- (4- {methyl - [(2-phenylamino-benzoxazol-6-yl) -acetyl] -amino} -phenyl) - pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] acetyl-amino} phenyl) -1- (thiophen-2-carbonyl) -pyrroli din-3-carboxylic acid;
1- (pyridine-4-carbonyl) -4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1- (morpholin-4-yl-acetyl) -4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- (4- {2- [2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetylamino} -phenyl ) -pyrrolidin-3-carboxylic acid;
1-acetyl-4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetyl} -amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetyl} -amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetyl} -amino) -phenyl] -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] acetyl} amino) phenyl] -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetyl} -amino) -phenyl] -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
1- (5-methyl-2,5-dihydro-isoxazol-3-carbonyl) -4- [4- (methyl - {[2- (pyridin-3-ylamino) benzoxazol-6-yl] -acetyl} - amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [2- (2-chloro-6-methylphenylamino) benzoxazole-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- (4- {2- [2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
4- (4- {2- [2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (thiophen-2-carbonyl) -pyrrolidin-3- carboxylic acid;
4- (4- {2- [2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (pyridin-4-carbonyl) -pyrrolidin-3- carboxylic acid;
4- (4- {2- [2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (morpholin-4-yl-acetyl) pyrrolidine 3-carboxylic acid;
4- (4- {2- [2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetylamino} -phenyl) -1- (5-methyl-2,5-dihydro-isoxazole -3-carbonyl) -pyrrolidine-3-carboxylic acid;
1-acetyl-4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
1-benzoyl-4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (thiophen-2-carbonyl) - pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (pyridin-4-carbonyl) - pyrrolidine-3-carboxylic acid;
4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) phenyl] -1- (morpholin-4-yl-acetyl ) -pyrrolidin-3-carboxylic acid;
4- [4 - ({[2- (2-chloro-6-methyl-phenylamino) benzoxazol-6-yl] -acetyl} -methyl-amino) -phenyl] -1- (5-methyl-2,5 dihydro-isoxazol-3-carbonyl) -pyrrolidine-3-carboxylic acid;
and their prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of such compounds and their prodrugs.

Preferred compounds of the invention are:
1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1-Acetyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
1- (3-carboxy-propionyl) -4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid;
and their prodrugs and pharmaceutically acceptable salts and solvates (for example hydrates) of such compounds and their prodrugs.

The Compounds of the invention show a useful pharmacological action and are consequently in pharmaceutical Compositions are incorporated and used in the treatment of Patients suffering from certain medical disorders used. The The present invention thus provides, according to a further aspect, compounds of the invention and compositions providing the compounds of the invention for use in therapy.

links within the scope of the present invention Interaction of the ligand VCAM-1 with its integrin receptor VLA-4 (α4β1) according to in Literature described in the literature and subsequently described in vitro and in vivo methods, and assuming the test results, that they interact with the pharmacological activity in humans and other mammals correlate. Thus, in another embodiment, the present invention Invention compounds of the invention and compositions containing the compounds of the invention, for use in the therapy of a patient suffering from conditions that alleviated by the administration of an inhibitor of α4β1 mediated cell adhesion can be suffers or for it susceptible is provided. For example, the compounds of the invention in the treatment of inflammatory Diseases, such as joint inflammation, including arthritis, rheumatoid arthritis, and other arthritic conditions, such as rheumatic spondylitis, gouty arthritis, traumatic arthritis, Rubella arthritis, psoriatic arthritis and osteoarthritis. additionally can the compounds in the treatment of acute synovitis, autoimmune diabetes, Autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular Disease, cardiovascular disease, multiple sclerosis, asthma, psoriasis, restenosis, myocarditis, inflammatory Bowel disease and melanoma cell division used in metastasis be.

A special embodiment the therapeutic invention Procedure is treating asthma.

A another special embodiment of therapeutic according to the invention Procedure is the treatment of joint inflammation.

A another special embodiment the therapeutic invention Method is treating inflammatory bowel disease.

According to one Another feature of the invention is the use of a compound of the invention in the manufacture of a medicament for treatment a condition caused by the administration of an inhibitor of Interaction of the ligand VCAM-1 at its integrin receptor VLA-4 (α4β1), for example conditions as described hereinabove. Such treatment includes the administration of an effective amount the compound of the invention or a compound of the invention containing composition to the patient. "Effective amount" is intended to include a quantity of the compound of the invention describe inhibiting the interaction of the ligand VCAM-1 to its integrin receptor VLA-4 (α4β1) is effective, and thus generating the desired therapeutic effect.

information For the purposes of treatment, it should be understood that they are prophylactic Include therapy as well as treatment of established conditions.

The present invention includes within its scope include pharmaceutical compositions, the at least one of the compounds of the invention in combination with a pharmaceutically acceptable carrier or excipients.

The Compounds of the invention can be administered by any suitable means. In practice can the compounds of the invention generally parenteral, local, rectally, orally or by inhalation, especially by oral Way, be administered.

The compositions of the invention may be prepared according to conventional methods using one or more pharmaceutically acceptable excipients or excipients. The adjuvants include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more agents selected from the group consisting of sweetening, flavoring, coloring or Stabilizers to obtain pharmaceutically acceptable preparations contain. The selection of carrier and the content of active substance in the carrier are generally determined according to the solubility and chemical properties of the active ingredient, the particular mode of administration and the requirements to be observed in the pharmaceutical practice. For example, excipients such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrants such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used for tabletting purposes. To make a capsule, it is advantageous to use lactose and high molecular weight polyethylene glycols. If aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate the suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof may also be used.

to parenteral administration are emulsions, suspensions or solutions the products of the invention in vegetable oil, for example sesame oil, peanut oil or olive oil, or aqueous-organic Solutions, such as water and propylene glycol, injectable organic esters, such as ethyl oleate, as well as sterile aqueous solutions the pharmaceutically acceptable Salts applied. The solutions the salts of the products according to the invention are especially for administration by intramuscular or Subcutaneous injection usable. The aqueous solutions, which are also solutions of Salts in pure distilled water may be used for intravenous administration be, with the proviso, that their pH is suitably adjusted; that means, you are expediently buffered and with a sufficient amount of glucose or sodium chloride isotonic and that they are made by heating, irradiation or Microfiltration be sterilized.

To the local Administration can Gels (water or alcohol base), creams or ointments containing the Compounds of the invention to be used. The compounds of the invention may also in a gel or matrix base for the application of a plaster be incorporated, resulting in a controlled release of the compound through the transdermal barrier.

to Administration by inhalation can the compounds of the invention in a suitable carrier for use in a sprayer or a suspension or solution aerosol solved or can be suspended, or can on a suitable solid support absorbed for use in a dry powder inhaler or adsorbed.

firm Compositions for rectal administration include suppositories, the according to known Are formulated methods and at least one compound of the invention included, one.

Of the Percentage of active ingredient of the compositions of the invention can be varied, it is necessary that he make up a share should, so that a suitable dosage should be obtained. Of course, different ones Dosage unit forms administered at approximately the same time become. The applied dose is determined by the doctor and depends on the desired one Therapy effect, the route of administration and the duration of treatment and the condition of the patient. In adults, the doses are in Generally about 0.001 to about 50, preferably about 0.001 to about 5 mg / kg, body weight per Day by inhalation, about 0.01 to about 100, preferably 0.1 to 70, in particular 0.5 to 10 mg / kg, body weight per day by oral Administration, and about 0.001 to about 10, preferably 0.01 to 1 mg / kg, body weight by intravenous daily Administration. In each case doses are calculated according to factors that determines for characteristic of the patient to be treated, such as age, Weight, general health and other characteristics, which can affect the effectiveness of the medical product.

The Compounds of the invention can so often administered as necessary to obtain the desired therapeutic effect. Some patients can quickly to a higher one or lower dose can react and get much weaker, preserved Doses as sufficient. For other patients it can be necessary that long-term treatments at the rate of 1 to 4 doses per day, according to the physiological requirements the respective patient. In general, the effective Product be administered orally 1 to 4 times a day. Of course it will it for Some patients may be necessary, not more than one or two doses prescribe per day.

The Compounds of the invention can by the application or adaptation of known methods, with those used to date or described in the literature For example, those described by R.C. Larock in Comprehensive Organic Transformations, VCH Publishers, 1989 become.

In The reactions described below may require reactive functional groups, for example hydroxy, amino, Imino, thio or carboxy groups, if present in the final product he wishes are to their unwanted To avoid participation in the reactions. Conventional protection groups may be in accordance with standard practice he wishes be; for example, see T.W. Greene and P.G.M. Wuts in "Protective Groups in Organic Chemistry "John Wiley and Sons, 1991.

Compounds of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ³ , as hereinbefore defined, and when Y is carboxy, may be prepared by hydrolysis of esters of formula (I), wherein R is ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is a group -CO ₂ R ²⁰ (wherein R ^{20 is} alkyl, alkenyl or arylalkyl). The hydrolysis may conveniently be carried out by alkaline hydrolysis using a base such as an alkali metal hydroxide, for example sodium hydroxide or lithium hydroxide, or an alkali metal carbonate, for example potassium carbonate, in the presence of an aqueous / organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol. at a temperature from about ambient to about reflux temperature. The hydrolysis of the esters may also be carried out by acid hydrolysis using an inorganic acid such as hydrochloric acid in the presence of an aqueous / inert organic solvent mixture using organic solvents such as dioxane or tetrahydrofuran at a temperature of from about 50 ° C to about 80 ° C be executed.

As another example, compounds of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as defined hereinabove and wherein Y is carboxy, may be prepared by acid catalyzed removal of the tert-butyl group from tert-butyl ester of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is a group -CO ₂ R ²⁰ (wherein R ^{20 is} tert -butyl) using standard reaction conditions, for example, reaction with trifluoroacetic acid at a temperature of about room temperature.

As another example, compounds of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is carboxy, may be prepared by hydrogenating compounds of formula (I), wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is a group -CO ₂ R ²⁰ (wherein R ^{20 is} arylmethyl, for example benzyl). The reaction may be carried out in the presence of ammonium formate and a suitable metal catalyst, for example palladium supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol, and at a temperature of about reflux temperature. Alternatively, the reaction may be carried out in the presence of a suitable metal catalyst, for example platinum or palladium, optionally supported on an inert support such as carbon, preferably in a solvent such as methanol or ethanol. This reaction is particularly suitable for compounds of formula (I) wherein L ¹ does not contain carbon-carbon multiple bonds.

In a method A can Compounds of formula (I) containing an amide bond by coupling an acid (or an acid halide) with an amine to obtain an amide bond, using of standard peptide coupling methods, as described hereinafter, getting produced.

worin R¹¹, R²⁰, Ar¹, A¹, A² und A³ wie hierin vorstehend definiert sind, mit Verbindungen der Formel (III): R¹-R¹²-C(=O)-X⁴ (III),worin R¹ und R¹² wie hierin vorstehend definiert sind und X⁴ eine Hydroxygruppe oder ein Halogen, vorzugsweise Chloratom, darstellt, hergestellt werden. Wenn X⁴ eine Hydroxygruppe darstellt, kann die Reaktion unter Verwendung von Standard-Peptidkupplungsverfahren, beispielsweise Kuppeln in Gegenwart von Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphoniumhexafluorophosphat und Triethylamin (oder Diisopropylethylamin) und Dimethylaminopyridin in Tetrahydrofuran (oder Dimethylformamid), bei Raumtemperatur ausgeführt werden. Wenn X⁴ ein Halogenatom darstellt, kann die Acylierungsreaktion mit Hilfe einer Base, wie Pyridin, vorzugsweise in einem Lösungsmittel, wie Tetrahydrofuran, und bei einer Temperatur bei etwa Raumtemperatur ausgeführt werden.As an example of method A, compounds of formula (I) wherein R ¹ , Ar ¹ , R ¹ , A ² and A ^{3 are} as hereinbefore defined, L ¹ -R ¹² -R ¹³ - (wherein R ^{12 is} as herein is defined above and R ^{13 is} -C (= O) -NR ¹¹ -) and Y is a group -CO ₂ R ²⁰ (wherein R ^{20 is} as defined hereinbefore) by reaction of compounds of the formula

wherein R ¹¹ , R ²⁰ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined, with compounds of formula (III): R ¹ -R ¹² -C (= O) -X ⁴ (III), wherein R ¹ and R ^{12 are} as hereinbefore defined and X ^{4 represents} a hydroxy group or a halogen, preferably chlorine atom. When X ^{4 represents} a hydroxy group, the reaction may be carried out using standard peptide coupling methods, for example, coupling in the presence of benzotriazol-1-yl-oxy-tris (dimethylamino) phosphonium hexafluorophosphate and triethylamine (or diisopropylethylamine) and dimethylaminopyridine in tetrahydrofuran (or dimethylformamide), be carried out at room temperature. When X ^{4 represents} a halogen atom, the acylation reaction may be carried out by means of a base such as pyridine, preferably in a solvent such as tetrahydrofuran, and at a temperature at about room temperature be executed.

worin R¹, L¹ und Ar¹ wie hierin vorstehend definiert sind, Y Carboxy darstellt und einer von A¹, A² und A³ NH darstellt und die anderen C(R³)(R⁴) wiedergeben, mit Verbindungen der Formel (V): R⁸-C(=O)-X⁵ (V),worin R⁸ wie hierin vorstehend definiert ist und X⁵ ein Halogen, vorzugsweise Chloratom, darstellt, hergestellt werden. Die Acylierungsreaktion kann geeigneterweise unter Standardreaktionsbedingungen, beispielsweise jene hierin vorstehend beschriebenen, ausgeführt werden.As another example of method A, compounds of formula (I) wherein R ¹ , L ¹ , Ar ^{1 are} as hereinbefore defined, Y represents carboxy and one of A ¹ , A ² and A ³ NR ² (wherein R ² -C (= O) -R ⁸ ), although the other C (R ³ ) (R ⁴ ) represent, by reaction of compounds of formula (IV):

wherein R ¹ , L ¹ and Ar ^{1 are} as hereinbefore defined, Y is carboxy and one of A ¹ , A ² and A ^{3 is} NH and the other C (R ³ ) (R ⁴ ) represent compounds of the formula ( V): R ⁸ -C (= O) -X ⁵ (V), wherein R ^{8 is} as hereinbefore defined and X ^{5 is} a halogen, preferably chlorine atom. The acylation reaction may suitably be carried out under standard reaction conditions, for example those described hereinabove.

Esters of formula (I) wherein R ¹ , L ¹ , Ar ^{1 are} as hereinbefore defined, Y is a group -CO ₂ R ²⁰ (wherein R ^{20 is} as hereinbefore defined) and one of A ¹ , A ² and A ³ NR ² (wherein R ^{2 represents} -C (= O) -R ⁸ ) while the others represent C (R ³ ) (R ⁴ ) similarly by reaction of compounds of formula (IV) wherein R is ¹ , L ¹ and Ar ^{1 are} as hereinbefore defined, Y represents a group -CO ₂ R ²⁰ (wherein R ^{20 is} as hereinbefore defined), and one of A ¹ , A ² and A ^{3 represents} NH, while the others C (R ³ ) (R ⁴ ), with compounds of formula (V) wherein R ^{8 is} as hereinbefore defined and X ^{5 represents} a hydroxy group or a halogen, preferably chlorine atom, using standard reaction conditions, for example those which are described hereinbefore.

According to one Another feature of the present invention, the compounds of the invention by mutual conversion of the other compounds of the invention getting produced.

For example, compounds of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is -C (= O) -NHOH may be prepared by reaction of compounds of formula (I) wherein R ¹ , L ¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and Y is carboxy, with hydroxylamine, by standard peptide coupling methods such as treatment with a carbodiimide, for example dicyclohexylcarbodiimide, in the presence of triethylamine, in an inert solvent such as dichloromethane or tetrahydrofuran, and at a temperature of about room temperature. The coupling can be carried out using 1-hydroxybenzotriazole and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide in dichloromethane at room temperature. The preparation can also be carried out using an O-protected hydroxylamine, such as O- (trimethylsilyl) hydroxylamine, O- (t-butyldimethylsilyl) hydroxylamine or O- (tetrahydropyranyl) hydroxylamine, followed by treatment with acid.

When another example of the mutual conversion process may be the compounds of the invention, which contain a heterocyclic group, wherein the heteroatom represents a nitrogen atom to which corresponding N-oxides are oxidized become. The oxidation may suitably be carried out by means of a reaction with a mixture of hydrogen peroxide and an organic acid, for example Acetic acid, preferably at or above room temperature, for example at a temperature of about 60-90 ° C, to be performed. Alternatively, the oxidation may be by reaction with a peracid, for example peracetic acid, or m-chloroperoxybenzoic acid, in an inert solvent, such as chloroform or dichloromethane, at a temperature of about Room temperature to reflux, preferably at elevated Temperature, running. Alternatively, the oxidation may be by reaction with hydrogen peroxide in the presence of sodium tungstate at temperatures between room temperature and about 60 ° C accomplished become.

Of course, the compounds of the invention may contain asymmetric centers. These asymmetric centers may be independently in either the R or S configuration. It will be clear to the person skilled in the art that certain compounds according to the invention also have geometric isomes you can show. It will be understood that the present invention includes individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures of the compounds of formula (I) hereinabove. Such isomers may be separated from mixtures thereof by the application or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or they may be prepared separately from the appropriate isomers of their intermediates. As an example, compounds of formula (I) wherein Y is carboxy may be reacted with camphorsulfame followed by resolution of the diastereoisomers and then regeneration of the individual isomers of the compounds of formula (I) by treatment with aqueous sodium hydroxide solution in methanol at a temperature of about room temperature be coupled.

According to one further feature of the invention Acid addition salts the compounds of the invention by reaction of the free base with the appropriate acid the application or adaptation made by known methods become. For example, you can the acid addition salts the compounds of the invention either by dissolution the free base in water or water alcohol solution or other suitable solvents, which is the appropriate acid and isolating the salt by evaporation of the solution, or by reacting the free base and acid in an organic solvent, in which case the salt is separated directly, are prepared, or can by concentration of the solution to be obtained.

The Acid addition salts according to the invention the connections can from the salts by application or adaptation of known methods be regenerated. For example, the parent compounds of the invention from their acid addition salts by treatment with an alkali, for example aqueous sodium or aqueous Ammonia solution, be regenerated.

The Compounds of the invention can from their base addition salts by application or adaptation be regenerated by known methods. For example, the Inventive compounds of the invention from their base addition salts by treatment with an acid, for example Hydrochloric acid, be regenerated.

The Compounds of the invention can suitably prepared or during the process according to the invention as solvates (for example, hydrates) are formed. The hydrates the compounds of the invention can expediently by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxane, tetrahydrofuran or methanol.

According to one another feature of the invention can the base addition salts of the compounds of the invention by reaction the free acid with the appropriate base by the application or adaptation of known Process are produced. For example, the base addition salts the compounds of the invention either by dissolution the free acid in water or aqueous alcoholic solution or other suitable solvents, containing the appropriate base, and isolating the salt by Evaporation of the solution or by reacting the free acid and base in an organic solvent, in which case the salt is separated directly, are produced, or can by concentration of the solution to be obtained.

The Starting materials and intermediates may be by application or adaptation by known methods, for example methods, as in the Reference Examples or their usual chemical equivalents described methods.

worin R²⁰, Ar¹, A¹, A² und A³ wie hierin vorstehend definiert sind, hergestellt werden. Die Reduktion kann geeigneterweise unter Verwendung von Standardverfahren für die Reduktion von aromatischen Nitroverbindungen zu den entsprechenden aromatischen Aminen, beispielsweise (i) Behandlung mit Zinnchlorid in einem inerten Lösungsmittel, wie Essigsäureethylester oder Dimethylformamid, bei einer Temperatur von etwa 70°C, (ii) Behandlung mit Zinn in Gegenwart von Salzsäure in Ethanol, bei einer Temperatur von etwa Rückflusstemperatur, oder (iii) Hydrierung in Gegenwart von Palladium-auf-Kohlenstoff, ausgeführt werden.Compounds of formula (II) wherein R ²⁰ , Ar ¹ , A ¹ , A ² and A ^{3 are} as hereinbefore defined and R ^{11 is} hydrogen may be prepared by reduction of the corresponding nitro compounds of formula (1):

wherein R ²⁰ , Ar ¹ , A ¹ , A ² and A ^{3 are} as defined hereinbefore. The reduction can ge suitably using standard procedures for the reduction of aromatic nitro compounds to the corresponding aromatic amines, for example (i) treatment with stannous chloride in an inert solvent such as ethyl acetate or dimethylformamide at a temperature of about 70 ° C, (ii) treatment with tin in Presence of hydrochloric acid in ethanol, at a temperature of about reflux temperature, or (iii) hydrogenation in the presence of palladium-on-carbon.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, represent A ¹ , A ² and A ³ NR ² [wherein R ^{2 represents} -C (= O) -R ⁸ ) and the other C ( R ³ ) (R ⁴ ) can be prepared by reacting compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, one A ¹ , A ² and A ^{3 represent} NH and the other C (R ³ ) (R ⁴ ), with compounds of the formula (2): R ⁸ -C (= O) -X ⁶ (2), wherein R ^{8 is} as hereinbefore defined and X ^{6 represents} a hydroxy group or a halogen, preferably chlorine atom. The reaction may be carried out by standard peptide coupling or acylation methods, for example those described hereinabove.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, represent A ¹ , A ² and A ³ NR ² [wherein R ^{2 is} -C (= O) -OR ^8a ] and the other C (R ³ ) (R ⁴ ) may be prepared by reacting compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as defined hereinabove, represent A ¹ , A ² and A ³ NH and the other C (R ³ ) (R ⁴ ), with compounds of the formula (3): R ^{8a is} OC (= O) -Cl (3), wherein R ^{8a is} as defined hereinbefore. The reaction may be carried out by standard acylation methods, for example those described hereinabove.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, represent A ¹ , A ² and A ³ NR ² [wherein R ^{2 represents} R ^8b ] and the other C (R ³ ) (R ⁴ can represent, by reaction of compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, one A ¹ , A ² and A ^{3 represent} NH and represent the other C (R ³ ) (R ⁴ ) , with compounds of the formula (4): R ^8b -X ⁷ (4), wherein R ^{8b is} as hereinbefore defined and X ^{7 represents} a hydroxy group or a halogen, preferably chlorine atom. The reaction may be carried out by standard alkylation methods, for example those described hereinabove.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as defined hereinabove, represent A ¹ , A ² and A ³ NH and represent the other C (R ³ ) (R ⁴ ) may be prepared by reaction of compounds of the Formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, A ¹ , A ² and A ^{3 represent} NC (= O) -O-CH = CH ₂ and the other C (R ³ ) (R ⁴ ) with a mineral acid such as hydrochloric acid in an inert solvent such as dioxane at a temperature of about room temperature.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, represent A ¹ , A ² and A ³ NC (= O) -O-CH = CH ₂ and the other C (R ³ ) ( R ⁴ ) may be prepared by reacting compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, one A ¹ , A ² and A ^{3 represent} N-CH ₂ Ph and the other C (R ³ ) (R ⁴ ) can be prepared with a vinyl chloroformate at the reflux temperature.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, A ¹ and A ^{3 are} CH ₂ , A ² N-CH ₂ Ph, may be prepared by reaction of compounds of formula (5): O ₂ N-Ar ¹ -CH = CH-CO ₂ R ²⁰ (5), wherein R ²⁰ and Ar ^{1 are} as defined hereinbefore, with N- (butoxymethyl) -N- (trimethylsilylmethyl) benzylamine, in the presence of trifluoroacetic acid and at a temperature at about room temperature.

Compounds of formula (1) wherein R ²⁰ and Ar ^{1 are} as hereinbefore defined, A ² and A ³ CH ₂ as and A ^{1 represents} NC (= O) -R ⁸ , can be obtained by reaction of compounds of formula (6): O ₂ N-Ar ¹ -CH = N-CH ₂ SiMe ₃ (6), wherein Ar ^{1 is} as hereinbefore defined with an acrylate ester of formula (7): CH ₂ = CH-CO ₂ R ²⁰ (7), wherein R ^{20 is} as hereinbefore defined and an acid chloride of formula (2) wherein R ⁸ and X ^{6 are} as hereinbefore defined, are prepared in an inert solvent such as tetrahydrofuran and at a temperature of about reflux temperature.

Compounds of formula (6) wherein Ar ^{1 is} as hereinbefore defined can be prepared by the application or adaptation of the methods of K. Achiwa et al., Chem. Pharm. Bull., 1983, 31, p. 3939.

Compounds of formula (IV) wherein R ¹ , L ¹ and Ar ^{1 are} as hereinbefore defined, Y is carboxy and one of A ¹ , A ² and A ^{3 is} NH, while the other C (R ³ ) (R ⁴ by hydrogenation of compounds of formula (I) wherein R ¹ , L ¹ and Ar ^{1 are} as hereinbefore defined, Y is carboxy and one of A ¹ , A ² and A ^{3 is} NCH ₂ Ph, while the other C (R ³ ) (R ⁴ ). The hydrogenation may suitably be carried out in the presence of palladium hydroxide in acetic acid under pressure and at a temperature of about room temperature.

intermediates of formulas (II), (IV) and (1) are novel compounds and as such do them and theirs herefor the preparation described method further features of the present invention Invention.

intermediates of the formula (IV) are also capable of the interaction of VCAM-1 and to control fibronectin with the integrin VLA-4.

The The present invention is further exemplified, however not to the explanatory below Examples and reference examples limited.

¹ H NMR spectra at 600 MHz were recorded on a DMX 600 Bruker. ¹ H NMR spectra at 500 MHz were recorded on a DRX 500 Bruker. ¹ H NMR spectra at 400 MHz were recorded on DRX 400 Bruker. ¹ H NMR spectra at 300 MHz were recorded on an AC 300 Bruker. ¹ H NMR spectra at 250 MHz were recorded on an AC 250 Bruker. b = broad signal, bd = broad doublet, bs = broad singlet, bt = broad triplet, d = doublet, dd = double doublet, m = multiplet, s = singlet, t = triplet, 2bs = two broad singlets, 2d = two doublets , 2m = two multiplets, 2s = two singlets.

Desorption Chemical Ionization Mass Spectra, MS (DCI) were on a Finnigan SSQ 7000 spectrometer, using ammonia as the reactant gas, recorded.

Electron impact mass spectra, MS (EI), were on a Finnigan SSQ 7000 spectrometer at 70 eV recorded.

Nearly Atom Bombardment Mass Spectra, MS (FAB), were used on a Autospec Micromass recorded.

Liquid Secondary Ion Mass Spectra, MS (LSIMS), were used on a VG Autospec spectrometer, using a mixture of glycerol thioglycerol 50:50 as the matrix, recorded.

EXAMPLE 1

1-Acetyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A solution of ethyl 1-acetyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylate (1.62 Reference Example 1) in anhydrous ethanol (60 ml) was treated dropwise with sodium hydroxide solution (48 ml, 0.1 M). After stirring for 15 hours at 23 ° C, the mixture became evaporated (40 ° C and 2.7 kPa). The residue was diluted with distilled water (200 ml), then cooled to 5 ° C and then the pH of the mixture was adjusted to 2 by the dropwise addition of hydrochloric acid (1N) to give the precipitation of a white solid. After stirring at 23 ° C for 15 hours, the mixture was filtered. The white solid was dried under reduced pressure (2.7 kPa), then triturated with ether to afford the title compound (1 g) as a white solid, m.p. 242 ° C. ¹ H-NMR [600 MHz, (CD ₃ ) ₂ SO]: δ 1.95 and 1.98 (2s, 3H); 2.25 (s, 3H); 3.10 to 3.95 (m, 6H); 3.58 (s, 2H); 3.89 (s, 3H); 6.85 (bd, J = 8Hz, 1H); 6.95 (t, J = 7.5Hz, 1H); 7.02 (bs, 1H); 7.13 (t, J = 7.5Hz, 1H); 7.17 (d, J = 7.5Hz, 1H); 7.25 and 7.28 (2d, J = 8Hz, 2H); 7.50 to 7.60 (m, 2H); 7.80 (d, J = 7.5Hz, 1H); 8.04 (d, J = 8Hz, 1H); 8.48 (s, 1H); 8.59 (s, 1H). MS [FAB (meta-nitrobenzyl alcohol)]: 545 [M + H] ⁺ .

EXAMPLE 2

1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A stirred solution of ethyl 1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylate (5 g Reference Example 7) in ethanol (60 ml) at 23 ° C was treated dropwise with sodium hydroxide solution (16 ml, 1N). After stirring for 24 hours, the mixture was evaporated (40 ° C and 2.7 kPa) and the residue was treated with water (300 ml). The mixture was cooled to 10 ° C, then treated with hydrochloric acid (25 ml, 1N) and then allowed to stand at 23 ° C for 20 hours. The resulting white precipitate was filtered, then dried under reduced pressure (40 ° C and 2.7 kPa) for 45 minutes and then recrystallized from aqueous ethanol (40 ml) to afford the title compound (3.25 g) as a white crystalline Powder, mp 248 ° C. TLC: R _F = 45/78 (on silica gel eluting with a mixture of dichloromethane and methanol, 90:10). ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO at 373 ° K]: δ 2.29 (s, 3H); 3.26 (m, 1H); 3.50 to 3.65 (m, 2H); 3.61 (s, 2H); 3.76 (m, 1H); 3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 6.88 (d, J = 8Hz, 1H); 6.99 (t, J = 7.5 Hz, 1H); 7.03 (bs, 1H); 7.14 (t, J = 7.5Hz, 1H); 7.18 (d, J = 7.5Hz, 1H); 7.26 (d, J = 8.5Hz, 2H); 7.45 (m, 3H); 7.55 (m, 4H); 7.70 (d, J = 7.5Hz, 1H); 8.01 (d, J = 8Hz, 1H); 8.10 (bs, 1H); 8.26 (bs, 1H); 9.64 (bs, 1H); 11.50 to 12.30 (b, 1H). MS [FAB (meta-nitrobenzyl alcohol)]: 607 [M + H] ⁺ .

EXAMPLE 3

1- (3-carboxy-propionyl) -4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A stirred solution of 1- (3-ethoxycarbonyl-propionyl) -4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine Ethyl 3-carboxylate (0.3 g, Reference Example 10) in ethanol (3 ml) was treated dropwise with aqueous sodium hydroxide solution (1.8 ml and then 0.9 ml after 20 hours, 1N). After stirring at 20 ° C for an additional 2 hours, the mixture was evaporated (40 ° C and 2.7 kPa). The residue was treated with water (50ml), then cooled to 5 ° C and the pH of the mixture was adjusted to 2 by the dropwise addition of hydrochloric acid (10ml, 1N). The aqueous solution was triturated with ethyl acetate (50 ml) to afford the title compound (130 mg) as a white solid, m.p. 184 ° C. TLC: R _F = 0.5 (on silica gel eluting with a mixture of dichloromethane and methanol, 50:50). ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO at 413 ° K]: δ 2.31 (s, 3H); 2.50 to 2.60 (m, 4H); 3.20 (m, 1H); 3.46 (m, 1H); 3.55 to 3.70 (m, 2H); 3.63 (s, 2H); 3.85 to 4.00 (m, 2H); 3.90 (s, 3H); 6.90 (bd, J = 8Hz, 1H); 7.01 (t, J = 7.5Hz, 1H); 7.04 (bs, 1H); 7.15 (t, J = 7.5Hz, 1H); 7.20 (d, J = 7.5Hz, 1H); 7.26 (d, J = 8.5Hz, 2H); 7.54 (d, J = 8.5Hz, 2H); 7.66 (d, J = 7.5Hz, 1H); 7.98 (d, J = 8Hz, 1H); 8.01 (bs, 1H); 8.10 (bs, 1H); 9.36 (bs, 1H). MS: [FAB (glycerol + thioglycerol)]: 603 [M + H] ⁺ .

EXAMPLE 4

1-benzoyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A stirred solution of ethyl 1-benzoyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylate (0, 33 g, Reference Example 13) in a mixture of ethanol (4 ml) and acetonitrile (40 ml) was treated dropwise at 20 ° C with aqueous sodium hydroxide solution (0.15 ml, 10N). After stirring for 6 days, the mixture was filtered and the insoluble light brown solid was triturated twice with acetonitrile (5 ml) then twice with dichloromethane (2.5 ml) and then dried. The solid was dissolved in water (30 ml) and filtered. The filtrate was cooled to 5 ° C and the pH of the mixture was adjusted to 2 by the dropwise addition of hydrochloric acid (1.2 mL, 1N). The resulting white precipitate was filtered, then washed three times with water (5 ml), then twice with diisopropyl ether (10 ml), and then dried under reduced pressure (40 ° C. and 2.7 kPa) to afford the title compound (0.134 g) as an off-white powder, mp. 155 ° C (with decomposition). ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO at 383 ° K]: δ 2.15 (m, 2H); 2.27 (s, 3H); 2.96 (m, 1H); 3.59 (s, 2H); 3.75 (m, 2H); 3.89 (s, 3H); 5.32 (m, 1H); 6.87 (bd, J = 8Hz, 1H); 6.98 (t, J = 7.5Hz, 1H); 7.02 (d, J = 1.5Hz, 1H); 7.10 to 7.25 (m, 4H); 7.30 to 7.45 (m, 5H); 7.52 (d, J = 8.5Hz, 2H); 7.67 (d, J = 8Hz, 1H); 7.99 (d, J = 8Hz, 1H); 8.15 (bs, 1H); 8.21 (bs, 1H); 9.55 (bs, 1H). MS (ES): 629 [M + Na] ⁺ .

EXAMPLE 5

1-benzyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A stirred solution of ethyl 1-benzyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylate (2, 95 g, Reference Example 16) in a mixture of acetonitrile (150 ml) and ethanol (125 ml) at 50 ° C was slowly treated with aqueous sodium hydroxide solution (0.46 ml, 30%). After stirring for 8 hours at room temperature and then gentle stirring for one week, the mixture was filtered. The solid was washed with dichloromethane (30 ml), then dried under reduced pressure (2.7 kPa) and then treated with water (200 ml). The mixture was acidified by addition of hydrochloric acid (3.5 mL, 1 M), then allowed to stand at room temperature for 15 hours, then treated with ethyl acetate (400 mL) and then filtered to give the title compound (1.16 g) as a white powder, mp. 255 ° C. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO]: δ 2.27 (s, 3H); 2.45 to 2.60 (m, 1H); 2.80 to 3.00 (m, 4H); 3.49 (m, 1H); 3.57 (s, 2H); 3.58 and 3.68 (2d, J = 14Hz, 2H); 3.90 (s, 3H); 6.85 (bd, J = 8Hz, 1H); 6.95 (bt, J = 7Hz, 1H); 7.02 (bs, 1H); 7.05 to 7.20 (m, 2H); 7.20 to 7.30 (m, 3H); 7.30 to 7.40 (m, 4H); 7.52 (bd, J = 8Hz, 2H); 7.82 (bd, J = 8Hz, 1H); 8.04 (d, J = 8Hz, 1H); 8.48 (bs, 1H); 8.59 (bs, 1H); 10.07 (bs, 1H). MS (LSIMS): 593 [M + H] ⁺ .

EXAMPLE 6

1-Acetyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A stirred solution of ethyl 1-acetyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylate (2, 2 g, Reference Example 18) in ethanol (100 ml) was treated dropwise with aqueous sodium hydroxide solution (5.7 ml, 1 M). After stirring at room temperature for 20 hours, the mixture was evaporated at 40 ° C under reduced pressure (2.7 kPa). The residue was treated with water (300 ml) and this mixture was washed with ethyl acetate (50 ml). The pH of the aqueous phase was adjusted to 2 by the addition of hydrochloric acid (6.5 ml, 1M). The resulting white solid was centrifuged (3000 rpm for 5 minutes), then dried under reduced pressure to afford the title compound (1.56 g) as a white solid, mp 204 ° C. ¹ H-NMR [250 MHz, (CD ₃ ) ₂ SO]: δ 1.60 to 2.20 (very broad band, 3H); 2.13 (m, 2H); 2.29 (s, 3H); 2.89 (m, 1H); 3.60 (s, 2H); 3.72 (m, 2H); 3.91 (s, 3H); 5.19 (bs, 1H); 6.88 (dd, J = 8 and 2Hz, 1H); 6.97 (dt, J = 7.5 and 1Hz, 1H); 7.03 (d, J = 2Hz, 1H); 7.10 to 7.25 (m, 4H); 7.57 (very bd, J = 7.5 Hz, 2H); 7.72 (bd, J = 7.5Hz, 1H); 8.01 (d, J = 8Hz, 1H); 8.29 (bs, 1H); 8.32 (bs, 1H); 9.76 (bs, 1H). MS (ES): 567 (M + Na ⁺ ).

EXAMPLE 7

(-) - 1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A solution of N- {4- [1-benzoyl-4- (10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo [5.2.1.0.1.5] decane-4 carbonyl) -pyrrolidin-3-yl] -phenyl} -2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetamide (0.187 g, Reference Example 21, diastereoisomer B) in a mixture of Tetrahydrofuran (3 ml) and methanol (4 ml) at 23 ° C were treated with aqueous sodium hydroxide solution (0.4 ml, 1M). After stirring at 23 ° C for 20 hours, the reaction mixture was concentrated to remove the organic solvents. The remaining aqueous solution was washed twice with ethyl acetate (25 ml), then cooled to 5 ° C and then treated with concentrated hydrochloric acid (0.5 ml). After stirring at 23 ° C for 3 hours, the white precipitate was filtered off and reverse phase chromatography [3 consecutive injections of 0.5 ml mother liquor prepared from 150 mg crude and 1.6 ml acetonitrile, filtered through a 200 μm filter; Column UP3 ODB.10M, Uptisphere, C-18, 3μ ODB, 10 mm in diameter x 100 mm in length (Interchim, Montlucon, France); Gradient elution conditions using mixtures of acetonitrile and water, 0-10 minutes 93: 3, 11-20 minutes increased to 57:43, next 15 minutes 57:43; Flow rate 3 ml / min; UV detection at 254 nm]. The fractions containing the compound of R _F 17/53 (RP-DC C18 Merck, No. 1.15685, Darmstadt, Germany, acetonitrile: water 50:50, v / v) were combined and concentrated under reduced pressure (2.7 kPa) concentrated to give the title compound (53mg) as a white solid. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO], a mixture of rotamers at ambient temperature]: δ 2.26 (s, 3H); 3.20 to 3.40 (m, 1H); 3.45 to 3.60 (m, 2H); 3.57 and 3.59 (2s, all of 2H); 3.72 (m, 2H); 3.89 and 3.90 (2s, all of 3H); 3.90 to 4.05 (m, 1H); 6.85 (m, 1H); 6.95 (bt, J = 7.5 Hz, 1H); 7.01 and 7.03 (2 bs, all of 1H); 7.10 to 7.20 (m, 2H); 7.24 (d, J = 8 Hz, 1H); 7.30 (bd, J = 8 Hz, 1H); 7.40 to 7.60 (m, 7H); 7.80 (d, J = 8 Hz, 1H); 8.00 to 8.10 (m, 1H); 8.48 (bs, 1H); 8.59 (bs, 1H); 10.08 and 10.11 (2 bs, all of 1H); 12.40 to 12.80 (very bs, 1H). MS (LSIMS): 607 (M + H] ⁺ . [Α] ^D -41.1 (c = 0.51, dimethyl sulfoxide).

EXAMPLE 8

4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid

A solution of 1-benzyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid (0.4 g, Example 5) in acetic acid (10 ml) was hydrogenated under 30 bar at 20 ° C in the presence of palladium dihydroxide (0.4 g) for 20 hours. The reaction mixture was filtered through a pad of Celite and the layer was washed with acetic acid. The combined filtrate plus washings were evaporated and the residual orange oil was stirred with ethyl acetate (50 mL) for 20 hours, then filtered to give the title compound (0.21 g) as a white powder, m.p. 218 ° C. ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO plus a few drops CD ₃ COOD, 383 ° K]: δ 1.89 (broad band, 1H); 2.26 (s, 3H); 3.16 (very broad band, 2H); 3.50 to 3.70 (very broad band, 3H); 3.60 (s, 2H); 3.89 (s, 3H); 6.86 (bd, J = 8Hz, 1H); 6.95 (bt, J = 7.5Hz, 1H); 7.01 (bs, 1H); 7.05 to 7.20 (m, 2H); 7.27 (bd, J = 8Hz, 2H); 7.56 (bd, J = 8Hz, 2H); 7.72 (bd, J = 8Hz, 1H); 8.01 (d, J = 8Hz, 1H). MS (LSIMS): 503 [M + H] ⁺ .

REFERENCE EXAMPLE 1

1-Acetyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester.

A stirred solution of [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid (1.63 g, prepared as described in Example 52B of International Patent Application Publication Number WO 96/22966). in anhydrous tetrahydrofuran (80 ml) at 23 ° C under an argon atmosphere was treated with benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (2.3 g). After stirring for 1 hour, the mixture was treated with ethyl 1-acetyl-4- (4-amino-phenyl) -pyrrolidine-3-carboxylate (1.43 g, Reference Example 2), then with triethylamine (2.92 ml) and dimethylaminopyridine ( 0.1 g). The resulting mixture was stirred at 23 ° C for an additional 20 hours, then evaporated (40 ° C and 2.7 kPa). The residue was treated with ethyl acetate (200 ml) and the resulting solution was washed twice with water (100 ml), then with brine (100 ml), then with water, then dried over magnesium sulfate and then under reduced pressure (40 ° C , 2.7 kPa). The residual white foam was triturated with diethyl ether (50 ml) for 20 hours and the insoluble material was chromatographed on silica gel (500 g, 0.045-0.020 mm particle size, 60 mm internal diameter stainless steel column) eluting at 100 ml per minute with a mixture of Dichloromethane and methanol (95: 5, v / v) to afford the title compound (1.62g) as a white, foamy solid. TLC: R _F = 50:74 [on silica gel eluting with a mixture of dichloromethane and methanol (95: 5, v / v)]. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO]: δ 1.00 to 1.15 (m, 3H); 1.96 and 1.99 (2s, 3H); 2.26 (s, 3H); 3.15 to 3.70 and 3.80 to 4.00 (2m, 6H); 3.58 (s, 2H); 3.90 (s, 3H); 4.02 (m, 2H); 6.86 (dd, J = 8 and 1.5Hz, 1H); 6.95 (bt, J = 7.5Hz, 1H); 7.02 (d, J = 1.5Hz, 1H); 7.10 to 7.20 (m, 2H); 7.27 (m, 2H); 7.56 (m, 2H); 7.81 (d, J = 7.5Hz, 1H); 8.05 (d, J = 8Hz, 1H); 8.48 (s, 1H); 8.59 (s, 1H); 10.12 and 10.13 (2s, 1H). MS [DCI (reactant gas ammonia)]: 573 [M + H] ⁺ .

REFERENCE EXAMPLE 2

1-Acetyl-4- (4-amino-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of ethyl 1-acetyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (1.82 g, Reference Example 3) in ethyl acetate (69 ml) was treated portionwise with stannous chloride (6.7 g). then the mixture was heated to 70 ° C. After 8 hours, the mixture was cooled to 25 ° C and then treated with ice-water (300 ml). The pH of the mixture was adjusted to 9 by the addition of freshly prepared aqueous sodium bicarbonate solution (5%) to afford a white suspension which was filtered through a pad of celite. The filtrate was separated and the aqueous layer was extracted twice with ethyl acetate (50 ml) and the combined organics were dried over magnesium sulfate, then evaporated (40 ° C. and 2.7 kPa) to afford the title compound (1.58 g). as an orange oil that was used without further purification. TLC: R _F = 54:85 [on silica gel plates by elution with a mixture of dichloromethane and methanol (90:10, v / v)]. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO]: δ 1.00 to 1.15 (m, 3H); 1.95 and 1.97 (2s, 3H); 3.05 to 3.95 (m, 6H); 4.02 (m, 2H); 4.97 and 4.99 (2bs, 2H); 6.52 (m, 2H); 6.94 and 6.98 (2d, J = 8.5Hz, 2H).

REFERENCE EXAMPLE 3

1-Acetyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of ethyl 4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (2 g, Reference Example 4) in dry dichloromethane (40 ml) was treated with triethylamine (1.21 ml) at 23 ° C. After stirring for 5 minutes, the mixture was treated dropwise with a solution of acetyl chloride (0.62 ml) in dichloromethane (3 ml), and after stirring for a further 2 hours, the mixture was then treated with triethylamine (1 ml). Stirring was continued for 15 minutes, then the reaction mixture was treated with water (100 ml). The organic phase was separated, then washed with hydrochloric acid (50 ml, 1N), then with water (50 ml), then dried over magnesium sulfate and then evaporated (40 ° C. and 2.7 kPa), providing the title compound (1 , 82 g) as a brown oil. TLC: R _F = 65/80 [on silica gel plates eluting with a mixture of dichloromethane and methanol (90:10, v / v)]. ¹ H-NMR [300 MHz, (CDCl ₃ ): δ 1.05 to 1.25 (m, 3H); 2.08 and 2.10 (2s, 3H); 3.24 (m, 1H); 3.45 to 4.20 (m, 5H); 4.10 (m, 2H); 7.43 (m, 2H); 8.20 (m, 2H). MS [EI]: 306 [M] ⁺ .

REFERENCE EXAMPLE 4

4- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of 4- (4-nitro-phenyl) -pyrrolidine-1,3-dicarboxylic acid 3-ethyl ester 1-vinyl ester (6 g, Reference Example 5) in dioxane (30 ml) was added dropwise at 25 ° C with hydrochloric acid (15 ml, 4N). After stirring for 2 hours, the mixture was treated with another aliquot of hydrochloric acid (15 ml, 4N) and stirring was continued at 25 ° C for a further 2 hours. The reaction mixture was evaporated (40 ° C and 2.7 kPa) and the residue was heated to the reflux temperature with ethanol (30 ml) for 45 minutes. The mixture was cooled to room temperature, then evaporated and the residue was triturated with diethyl ether (100 ml) for 20 hours to afford the title compound (4.3 g) as a white solid. TLC: R _F = 25/70 [on silica gel plates eluting with a mixture of dichloromethane and methanol (90:10, v / v)]. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO]: δ 1.09 (t, J = 7 Hz, 3H); 3.25 to 3.85 (3m, 6H); 4.05 (m, 2H); 7.76 (d, J = 8.5Hz, 2H); 8.24 (d, J = 8.5Hz, 2H); 9.90 (b, 2H). MS [EI]: 264 [M] ⁺ .

REFERENCE EXAMPLE 5

4- (4-nitro-phenyl) -pyrrolidine-1,3-dicarboxylic acid 3-ethyl ester-1-vinylester

A stirred solution of ethyl 1-benzyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (9.56 g, Reference Example 6) in 1,2-dichloroethane (25 ml) was added at 25 ° C and under a Argon atmosphere was treated dropwise with vinyl chloroformate (2.5 ml). The resulting mixture was refluxed for 20 hours, then evaporated (40 ° C and 2.7 kPa). The residue was subjected to flash chromatography on silica gel (0.045-0.020 mm particle size) by elution with a mixture of cyclohexane and ethyl acetate (50:50, v / v) to afford the title compound (8.38 g) as a white solid. ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO]: δ 1.07 (m, 3H); 3.35 to 3.70 and 3.70 to 4.00 (2m, 6H); 4.03 (m, 2H); 4.54 and 4.56 (2d, J = 6Hz, 1H); 4.79 and 4.85 (2d, J = 14Hz, 1H); 7.16 (dd, J = 14 and 6Hz, 1H); 7.69 (d, J = 8Hz, 2H); 8.23 (d, J = 8Hz, 2H). MS [EI]: 334 [M] ⁺ .

REFERENCE EXAMPLE 6

1-Benzyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of 4-nitroethyl cinnamate (10 g) in dichloromethane (200 mL) was treated at 23 ° C with N- (butoxymethyl) -N- (trimethylsilylmethyl) benzylamine (10 g, prepared as described in Tetrahedron Letters, 1996, 37 (43 ), Pages 7743-7744), followed by immediate treatment with trifluoroacetic acid (0.25 ml). After stirring at 25 ° C for 20 hours, another aliquot of trifluoroacetic acid (0.5 ml) was added and stirring was continued for a further 20 hours. The reaction mixture was cooled to 5 ° C, then treated with sodium carbonate (5 g) and then filtered. The filtrate was concentrated under reduced pressure (40 ° C and 2.7 kPa) and then with anhydrous ethanol (250 ml) followed by oxalic acid (4.1 g). The mixture was triturated for 10 minutes, then stored at 25 ° C for 20 hours. The resulting white crystalline solid was filtered, then washed twice with ethanol (10 ml), then dried, then treated with water (600 ml). The pH of the mixture was adjusted to 6-7 by addition of potassium bicarbonate (10 g) over 30 minutes, then extracted with ethyl acetate (400 ml). The organic extract was dried over magnesium sulfate, then evaporated (40 ° C and 2.7 kPa) to afford the title compound (9.36 g) as an orange oil.
¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO]: δ 1.14 (t, J = 7Hz, 3H); 2.63 (m, 1H); 2.85 (m, 1H); 2.99 (m, 2H); 3.14 (m, 1H); 3.66 (AB system, J = 13Hz, 2H); 3.65 to 3.80 (m, 1H); 4.07 (m, 2H); 7.20 to 7.40 (m, 5H); 7.63 (d, J = 8.5Hz, 2H); 8.18 (d, J = 8.5Hz, 2H). MS [EI]: 354 [M] ⁺ .

REFERENCE EXAMPLE 7

1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of [3-methoxy-4- (3-o-tolylureido) -phenyl] -acetic acid (5.1 g) in anhydrous tetrahydrofuran (140 mL) at 23 ° C under an argon atmosphere was treated with benzotriazole-1. yloxytris (dimethylamino) phosphonium hexafluorophosphate (8.61 g). After stirring for 1 hour, the mixture was treated with ethyl 1-benzoyl-4- (4-amino-phenyl) -pyrrolidine-3-carboxylate (5.48 g, Reference Example 8), then triethylamine (9.1 mL), dimethylaminopyridine ( 0.2 g) and dimethylformamide (5 ml). The resulting mixture was stirred at 23 ° C for 2 days, then evaporated (40 ° C and 2.7 kPa). The residue was treated with ethyl acetate (300 ml) and the resulting solution was washed twice with water (200 ml), twice with hydrochloric acid (200 ml, 1N), then twice with aqueous sodium bicarbonate solution (200 ml, 10%), then with brine ( 100 ml), then with water (100 ml), then dried over magnesium sulfate and then evaporated (40 ° C and 2.7 kPa). The resulting white foam was triturated with diethyl ether (50 ml) for 20 hours to afford the title compound (9.6 g) as a white powder, mp 130 ° C. ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO at 383 ° K]: δ 1.15 (t, J = 7Hz, 3H); 2.30 (s, 3H); 3.33 (m, 1H); 3.50 to 3.70 (m, 2H); 3.62 (s, 2H); 3.77 (m, 1H); 3.85 to 4.00 (m, 2H); 3.91 (s, 3H); 4.10 (q, J = 7Hz, 2H); 6.89 (bd, J = 8Hz, 1H); 6.95 to 7.05 (m, 1H); 7.04 (d, J = 2Hz, 1H); 7.15 (t, J = 8Hz, 1H); 7.20 (d, J = 7.5Hz, 1H); 7.25 (d, J = 8Hz, 2H); 7.45 (m, 3H); 7.54 (m, 4H); 7.69 (d, J = 8Hz, 1H); 8.01 (d, J = 8Hz, 1H); 8.16 (s, 1H); 8.22 (s, 1H); 9.56 (s, 1H). MS [DCI] reactant gas ammonia)]: 635 [M + H] ⁺ .

REFERENCE EXAMPLE 8

4- (4-amino-phenyl) -1-benzoyl-pyrrolidin-3-carboxylate

A stirred solution of ethyl 1-benzoyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (10 g, Reference Example 9) in a mixture of ethyl acetate (324 ml) and ethanol (78 ml) was heated at 24 ° C treated in portions with stannous chloride (30.65 g), then heated to 80 ° C for 4 hours. After cooling to 24 ° C, the mixture was treated with water (400 ml) then with aqueous sodium bicarbonate solution (125 ml, 5%) and then filtered through a pad of Celite, washing twice with ethyl acetate (300 ml). The aqueous layer of the filtrate was separated and extracted twice with ethyl acetate (300 ml). The combined organic phases were dried over magnesium sulfate and evaporated (40 ° C and 2.7 kPa). The residue was triturated with diethyl ether (100 ml) to afford the title compound (5.48 g) as a white powder. ¹ H-NMR [250MHz, (CD ₃ ) ₂ SO at 383 ° K]: δ 1.14 (t, J = 7Hz, 3H); 3.24 (m, 1H); 3.40 to 3.60 (m, 2H); 3.73 (dd, J = 11 and 8.5Hz, 1H); 3.80 to 4.00 (m, 2H); 4.08 (q, J = 7Hz, 2H); 6.58 (d, J = 8Hz, 2H); 6.98 (d, J = 8Hz, 2H); 7.40 to 7.60 (m, 5H). MS [EI]: 338 [M] ⁺ .

REFERENCE EXAMPLE 9

1-benzoyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of ethyl 4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (7.5 g, Reference Example 4) in methylene chloride (100 ml) was treated dropwise with triethylamine (5.8 ml) at 23 ° C. After stirring for 15 minutes, the mixture was added dropwise with a solution of benzoyl chloride in a separate vessel by treating a stirred benzoic acid solution (5 g) in methylene chloride (15 ml) at 23 ° C with oxalyl chloride (5 ml) and stirring 2 hours evaporation of the reaction mixture] in methylene chloride (3.5 ml). The resulting dark brown mixture was stirred for 1.5 hours at 23 ° C, then filtered. The filtrate was washed successively with water (100 ml), then twice with hydrochloric acid (100 ml, 1N), then with brine (100 ml), then with water (100 ml), then dried over magnesium sulfate and then evaporated (40 ° C and 2.7 kPa) to afford the title compound (10 g) as a viscous oil. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO at 383 ° K]: δ 1.13 (t, J = 7Hz, 3H); 3.49 (m, 1H); 3.65 (m, 1H); 3.75 to 3.90 (m, 2H); 3.90 to 4.20 (m, 2H); 4.09 (m, 2H); 7.40 to 7.65 (m, 5H); 7.66 (d, J = 8.5Hz, 2H); 8.19 (d, J = 8.5Hz, 2H). MS [DCI (reactant gas ammonia)]: 369 [M + H] ⁺ , 386 [M + NH ₄ ] ⁺

REFERENCE EXAMPLE 10

1- (3-ethoxycarbonyl-propionyl) -4 (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid (0.189 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous tetrahydrofuran ( 5 ml) at 20 ° C and under argon atmosphere was treated with benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (0.318 g). After 20 minutes, the mixture was then extracted with 4- (4-amino-phenyl) -1- (3-ethoxycarbonyl-propionyl) -pyrrolidine-3-carboxylic acid, ethyl ester (5.48 g, Reference Example 11), followed by triethylamine (0.34 ml) and dimethylaminopyridine (0.007 g). The resulting mixture was stirred at 20 ° C for 20 hours, then evaporated (40 ° C and 2.7 kPa). The residue was treated with ethyl acetate (50 ml) and the resulting solution was washed with water (50 ml), then with citric acid (50 ml, 1N), then with aqueous sodium bicarbonate solution (50 ml, 10%), then with brine (50 ml), then with water (50 ml), then dried over magnesium sulfate and then evaporated (40 ° C and 2.7 kPa) to afford the title compound (0.3 g) as an off-white powder. TLC: R _F = 33/66 [on silica gel plates eluting with a mixture of dichloromethane and methanol (90:10, v / v)]. ¹ H-NMR [250MHz, (CD ₃ ) ₂ SO at 373 ° K]: δ 1.13 (t, J = 7Hz, 3H); 1.21 (t, J = 7Hz, 3H); 2.29 (s, 3H); 2.55 (bs, 4H); 3.2 to 3.75 (b, 4H); 3.60 (s, 2H); 3.80 to 4.10 (b, 2H); 3.90 (s, 3H); 4.09 (m, 4H); 6.87 (dd, J = 8.5 and 2Hz, 1H); 6.98 (t, J = 7.5Hz, 1H); 7.03 (d, J = 2Hz, 1H); from 7.10 to 7.25 (m, 2H); 7.25 (d, J = 8.5Hz, 2H); 7.56 (d, J = 8, 5Hz, 2H); 7.71 (d, J = 8Hz, 1H); 8.02 (d, J = 8.5Hz, 1H); 8.28 (bs, 1H); 8.31 (bs, 1H); 9.74 (bs, 1H). MS [ES]: 681 [M + Na] ⁺ .

REFERENCE EXAMPLE 11

4- (4-Amino-phenyl) -1- (3-ethoxycarbonyl-propionyl) -pyrrolidine-3-carboxylic acid ethyl ester

A solution of ethyl 1- (3-ethoxycarbonyl-propionyl) -4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (0.33 g, Reference Example 12) in acetic acid (5 ml) and 10% palladium on Activated charcoal (0.1 g) was stirred under a hydrogen atmosphere (1 bar) for 20 hours, then filtered through a pad of celite. The filtrate was evaporated (40 ° C and 2.7 kPa) to afford the title compound (0.218 g) as an oil. MS [DCI (reactant gas ammonia)]: 363 [M + H] ⁺ .

REFERENCE EXAMPLE 12

1- (3-ethoxycarbonyl-propionyl) -4- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred mixture of ethyl 4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (0.3g, Reference Example 4) and triethylamine (0.42ml) in dichloromethane (6ml) was added dropwise at 20 ° C with ethyl succinyl chloride (0.18 g). After stirring for 20 hours, the solution was washed twice with water (50 ml), then twice with brine (50 ml), then with water (50 ml), then dried over magnesium sulfate and then evaporated (40 ° C and 2.7 kPa) to afford the title compound (0.3 g) as a light brown oil. TLC: R _F = 51/81 [on silica gel plates eluting with a mixture of dichloromethane and methanol (90:10, v / v)]. MS [DCI (reactant gas ammonia)]: 393 [M + H] ⁺ .

REFERENCE EXAMPLE 13

1-benzoyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetic acid (1.35 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in anhydrous Tetrahydrofuran (60 ml) at 20 ° C and under argon atmosphere was treated with benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (2.04 g). After stirring for 10 minutes, the mixture was treated with 2- (4-amino-phenyl) -1-benzoylpyrrolidine-3-carboxylic acid methyl ester (1.5 g, b.p. Example 14), then treated with triethylamine (1.77 ml) and dimethylaminopyridine (0.051 g). The resulting mixture was stirred at 20 ° C for 60 hours, then evaporated (40 ° C and 2.7 kPa). The residue was dissolved in ethyl acetate (150 ml) and the solution was washed with water (100 ml) then with aqueous potassium bicarbonate solution (100 ml, 10%), then with water (50 ml), then dried over magnesium sulfate and then under reduced pressure (40 ° C and 2.7 kPa). The residue was subjected to flash chromatography on silica gel (200 g, 0.045-0.020 mm particle size) by elution with a mixture of cyclohexane and ethyl acetate (30:70, v / v) to afford the title compound (0.33 g) as an off-white powder , MS [DCI (reactant gas ammonia)]: 621 [M + H] ⁺ .

REFERENCE EXAMPLE 14

2- (4-Amino-phenyl) -1-benzoyl-pyrrolidin-3-carboxylic acid methyl- and 2- (4-amino-phenyl) -1-benzoyl-pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of 1-benzoyl-2- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid methyl ester (8.3 g, Reference Example 15) in a mixture of ethanol (150 ml) and hydrochloric acid (117 ml, 3N) the reflux temperature was treated with tin beads (8.3 g). After 1 hour, the mixture was cooled to 20 ° C, then treated with water (300 ml) and then the pH of the mixture was adjusted to 8 by addition of potassium bicarbonate (10 g). The mixture was triturated with ethyl acetate (300 ml) and filtered through a pad of Celite. The aqueous layer from the filtrate was separated and extracted twice with ethyl acetate (300 ml). The combined organic extracts were dried over magnesium sulfate and evaporated (40 ° C, 2.7 kPa). The residue was subjected to chromatography on silica gel (500 g, 0.020-0.045 mm particle size) using a 60 mm I.D. column and eluting with a mixture of dichloromethane and methanol (98: 2, v / v) at 120 ml / min to afford the title compounds (2.64 g) in a ratio of 1/3 methyl ester to 2/3 ethyl ester as determined by NMR spectroscopy. ¹ H-NMR [300 MHz, (CD ₃ ) ₂ SO at 383 ° K]: δ 1.04 (t, J = 7Hz, 2H); 2.00 to 2.45 (m, 2H); 3.29 (s, 1H); 3.40 to 4.00 (m, every 3H); 3.80 to 4.00 (m, 1.3H); 4.64 (b, 2H); 5.18 (m, 1H); 6.51 (m, 2H); 6.75 (m, 2H); 7.20 to 7.45 (m, 5H). MS (EI): 338 [M] ⁺ (ethyl ester); 324 [M] ⁺ (methyl ester).

REFERENCE EXAMPLE 15

1-benzoyl-2- (4-nitro-phenyl) -pyrrolidine-3-carbonsäuremethylester

A stirred solution of (4-nitrobenzylidene) -trimethylsilanylmethyl-amine (22 g, prepared as described in Chem. Pharm. Bull. 31 (11) p. 3939, 1893) in tetrahydrofuran (440 ml) at 45 ° C treated dropwise over 1.5 hours with a mixture of benzoyl chloride (10.1 ml) and methyl acrylate (9.3 ml) in tetrahydrofuran (500 ml). After stirring for 2.5 hours at 45 ° C, the mixture was allowed to cool to 20 ° C, then evaporated (40 ° C and 2.7 kPa). The residue was dissolved in ethyl acetate (800 ml) and the solution was washed with hydrochloric acid (500 ml, 1N), then with aqueous sodium hydroxide solution (500 ml, 1N), then with water (500 ml), then dried over magnesium sulfate and then evaporated (40 ° C and 2.7 kPa). The residue was subjected to chromatography on silica gel (500 g, 0.020-0.045 mm particle size) using a 60 mm I.D. column and eluting with a mixture of cyclohexane and ethyl acetate (80:20, v / v) at 100 ml / min. to afford the title compound (8.33 g) as a yellowish powder. ¹ H-NMR [500 MHz, (CD ₃ ) ₂ SO at 373 ° K]: δ 2.19 (m, 1H); 2.32 (m, 1H); 3.34 (s, 3H); 3.70 (m, 2H); 4.03 (m, 1H); 5.52 (m, 1H); From 7.35 to 7.50 (m, 7H); 8.12 (d, J = 8.5Hz, 2H). MS (EI): 354 [M] ⁺ .

REFERENCE EXAMPLE 16

1-benzyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of ethyl 1-benzyl-4- (4-amino-phenyl) -pyrrolidine-3-carboxylate (2.27 g, Reference Example 17), 3-methoxy-4- (3-o-tolyl-ureido) -phenyl ] -acetic acid (2.20 g) and benzotriazole-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (3.09 g) was treated with a mixture of triethylamine (3.58 ml) and 4-dimethylaminopyridine (85.5 mg) in Tetrahydrofuran (20 ml). After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate (200 mL), then washed with water (200 mL) and then washed with aqueous sodium bicarbonate solution (200 mL, 10%). The organic phase was dried over magnesium sulfate and then concentrated under reduced pressure (2.7 kPa). The residue was chromatographed on silica gel (500 g, 20-45 μm) eluting with a Mixture of cyclohexane and ethyl acetate (70:30, v / v). The fractions containing the compound R _F = 80/24 (thin layer chromatography plate, reference no. 05719, Merck KGaA, 64271 Darmstadt, Germany, 70:30, cyclohexane: ethyl acetate, v / v) were combined and concentrated under reduced pressure (2, 7 kPa) to give the title compound (2.95 g) as a whitish powder.

REFERENCE EXAMPLE 17

1-Benzyl-4- (4-amino-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A mixture of ethyl 1-benzyl-4- (4-nitro-phenyl) -pyrrolidine-3-carboxylate (15 g, Reference Example 6), tin (25.12 g), hydrochloric acid (230 ml, 3M) and ethanol (230 ml ) was heated at the reflux temperature for 1 hour. After cooling to room temperature, the pH of the mixture was adjusted to 9 by the addition of solid sodium carbonate. The mixture was then diluted with water to give a final volume of 1000 ml and then filtered through a pad of celite. The clear filtrate was extracted twice with ethyl acetate (1000 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The crude residue was subjected to chromatography using a Prochrom LC60 column, 40 cm bed of silica, 20-45 microns, eluting with a mixture of cyclohexane and ethyl acetate (70:30, v / v), and at 100 cm ³ / min flow rate , subjected. The fractions containing the compound with R _F 60/171 (thin layer chromatography plate, reference no. 05719, Merck KGaA, Darmstadt 64271, Germany, cyclohexane: ethyl acetate, 70:30, v / v) were combined and concentrated under reduced pressure (2.7 kPa ) to give the title compound (7.22 g) as a yellow oil.

REFERENCE EXAMPLE 18

1-Acetyl-2- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred suspension of 3-methoxy-4- (3-o-tolylureido) -phenyl] -acetic acid (1.73 g, prepared as described in Example 52B of International Patent Application Publication No. WO 96/22966) in tetrahydrofuran (60 ml ) was reacted with benzotriazolyl-N-oxy-tris (dimethylamino) phosphonium hexafluorophosphate (2.7 g), then with 4-dimethylaminopyridine (73 mg), then with triethylamine (3.1 ml) and then with 1-acetyl-2-one. (4-amino-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester (1.7 g, Reference Example 19). After stirring overnight at room temperature, the reaction mixture was diluted with water (100 ml), then extracted three times with ethyl acetate (100 ml). The organic extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica gel (20-45 μm) eluting with a mixture of dichloromethane and methanol (95: 5, v / v). The fractions containing the compound of R _F 32/144 (thin layer chromatography plate, reference no. 05719, Merck KGaA, 64271 Darmstadt, Germany, eluent dichloromethane: methanol, 95: 5, v / v) were combined and concentrated under reduced pressure (2.7 kPa) to dryness to afford the title compound (2.2 g) as a white powder.

REFERENCE EXAMPLE 19

1-Acetyl-2- (4-amino-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred mixture of ethyl 1-acetyl-2- (4-amino-phenyl) -pyrrolidine-3-carboxylate (3 g, Reference Example 20) and 10% palladium on charcoal in ethanol (150 ml) was added under atmospheric pressure for 4 Hydrogenated for hours at room temperature and then filtered through a pad of Celite. The filter layer was washed with ethanol (50 ml) and the combined filtrate plus washings were evaporated. The residue was subjected to flash chromatography on silica gel (330 g, 20-45 μm, 0.6 bar) eluting with a mixture of dichloromethane and methanol (95: 5, v / v). The fractions containing the compound of R _F 16/63 (thin layer chromatography plate, reference no. 05719, Merck KGaA, 64271 Darmstadt, Germany, dichloromethane: methanol, 95: 5, v / v) were combined and concentrated under reduced pressure (2.7 kPa ) to give the title compound (1.71 g).

REFERENCE EXAMPLE 20

1-Acetyl-2- (4-nitro-phenyl) -pyrrolidine-3-carboxylic acid ethyl ester

A stirred solution of (4-nitro-benzylidene) -trimethylsilanylmethyl-amine (3.2g) in tetrahydrofuran (120ml) at 40 ° C was treated with a solution of acetyl chloride (1ml) and ethyl acrylate (1.6ml) Tetrahydrofuran (60 ml). After stirring at 40 ° C for 20 hours, the reaction mixture was evaporated. The residual oil was treated with ethyl acetate (300 ml) and water (100 ml) and the mixture was then stirred for 20 hours. The organic phase was washed twice with water (100 ml), then dried and then concentrated under reduced pressure (2.7 kPa). The residue was subjected to flash chromatography on silica gel (700 g, 20-45 mm, 0.6 bar) eluting with a mixture of cyclohexane and ethyl acetate (90:10, v / v) to give the title compound (3.04 g). , R _F = 37/162, thin layer chromatography plate, reference no. 05719, Merck KGaA, 64271 Darmstadt, Germany.

REFERENCE EXAMPLE 21

N- {4- [1-benzoyl-4- (10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo [5.2.1.0.1.5] decan-4-carbonyl) - pyrrolidin-3-yl] phenyl} -2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetamide (Diastereoisomer A) and N- {4- [1-benzoyl-4- (10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo [5.2.1.0.1.5] decane 4-carbonyl) -pyrrolidin-3-yl] phenyl} -2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetamide (Diastereoisomer B)

• (i) N-{4-[1-Benzoyl-4-(10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo[5.2.1.0.1.5]decan-4-carbonyl)-pyrrolidin-3-yl]-phenyl}-2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetamid (Diastereoisomer A), (0,19 g), HPLC: R_T = 7,13 Minuten (ein Dynamax 60-A Silica Analytical Column Module, 8 μ, 4,6 × 250 mm, Bezug Nr. 83-101-C, verbunden mit Dynamax 60-A Silica Analytical Guard Module, 8 μ, 4,6 × 50 mm, Bezug Nr. 83-101-G (Rainin Instrument Company, Mack Road, Box 4026, Woburn, MA 01888-4026), durch Elution mit einem Gemisch von Dichlormethan und 2-Propylalkohol (96:4, Volumen/Volumen); Fließgeschwindigkeit 0,5 ml/Minute; UV-Detektion bei 254 nm). ¹H-NMR [400 MHz, (CD₃)₂SO, 383°K]: δ 0,96 (s, 3H); 1,04 (s, 3H); 1,30 (m, 1H); 1,47 (m, 1H); 1,70 bis 2,05 (m, 5H); 2,29 (s, 3H); 3,55 bis 3,65 (m, 3H); 3,61 (s, 2H); 3,74 (d, J=14,5Hz, 1H); 3,75 bis 3,95 (m, 3H); 3,91 (s, 3H); 4,00 (m, 1H); 4,10 (m, 1H); 6,89 (dd, J=8 und 2Hz, 1H); 7,00 (bt, J=8Hz, 1H); 7,04 (d, J=1,5Hz, 1H); 7,10 bis 7,25 (m, 2H); 7,22 (d, J=8,5Hz, 1H); 7,40 bis 7,60 (m, 7H); 7,70 (bd, J=8Hz, 1H); 8,01 (d, J=8Hz, 1H); 8,17 (bs, 1H); 8,23 (bs, 1H); 9,57 (bs, 1H). MS(LSIMS): 804[M+H]⁺.
• (ii) N-{4-[1-Benzoyl-4-(10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo[5.2.1.0.1.5]decan-4-carbonyl)-pyrrolidin-3-yl]-phenyl}-2-[3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetamid (Diastereoisomer B), (0,187 g). HPLC: R_T = 8,32 Minuten. ¹H-NMR [400 MHz, (CD₃)₂SO, 383°K]: δ 0,77 (s, 3H); 0,91 (s, 3H); 1,27 (m, 1H); 1,41 (m, 1H); 1,65 bis 2,00 (m, 5H); 2,29 (s, 3H); 3,50 bis 3,95 (m, 7H); 3,60 (s, 2H); 3,91 (s, 3H); 3,95 bis 4,05 (m, 2H); 6,87 (dd, J=8 und 2Hz, 1H); 6,99 (bt, J=8Hz, 1H); 7,03 (d, J=1,5Hz, 1H); 7,10 bis 7,25 (m, 2H); 7,23 (d, J=8,5Hz, 2H); 7,40 bis 7,60 (m, 7H); 7,69 (bd, J=8Hz, 1H); 8,00 (d, J=8Hz, 1H); 8,18 (bs, 1H); 8,23 (bs, 1H); 9,58 (bs, 1H). MS(LSIMS): 804[M+H]⁺.

A solution of racemic 1-benzoyl-4- (4- {2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetylamino} -phenyl) -pyrrolidine-3-carboxylic acid (2 g , Reference Example 22) in dimethylformamide (10 ml) at 23 ° C was treated with a solution of camphorsultam (0.709 g) in dimethylformamide (10 ml), then with O- (7-azabenzotriazol-1-yl) -N, N ', N'-tetramethyluronium hexafluorophosphate (1.3 g), then treated with triethylamine (10 ml) and then with 4-dimethylaminopyridine (50 mg). After stirring at 23 ° C for 20 hours, the reaction mixture was diluted with water (500 ml) and this mixture was acidified by addition of hydrochloric acid (10M). The resulting precipitate was filtered and then dried under reduced pressure (2.7 kPa) to afford 2 g of crude product. A portion (0.5g) of this material, dissolved in a mixture of dichloromethane (2.5ml) and 2-propyl alcohol (50μl), was chromatographed using a Dynamax 60-A Silica Preparative Column Module, 8μ, 21 , 4 in diameter × 250 mm in length, reference No. 83-121-C, connected to Dynamax 60-A Silica Preparative Guard Module, 8 μ, 21.4 in diameter × 50 mm in length, reference No. 83-121-G , (Rainin Instrument Company, Mack Road, Box 4026, Woburn, MA 01888-4026) and eluting with a mixture of dichloromethane and 2-propyl alcohol (96: 4, v / v) at a flow rate of 10 ml / minute and UV Detection at 254 nm; while two other portions (0.1 g) were subjected to similar chromatographic conditions, but by elution with a mixture of dichloromethane and 2-propyl alcohol (98: 2, v / v) at 10 ml / minute from 0 to 40 minutes and then elution with a mixture of dichloromethane and 2-propyl alcohol (96: 4, v / v) of 55 to 90 minutes to give:

• (i) N- {4- [1-Benzoyl-4- (10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo [5.2.1.0.1.5] decane-4 carbonyl) -pyrrolidin-3-yl] -phenyl} -2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetamide (diastereoisomer A), (0.19 g), HPLC: R _T = 7.13 minutes (a Dynamax 60-A Silica Analytical Column Module, 8 μ, 4.6 × 250 mm, reference No. 83-101-C, coupled to Dynamax 60-A Silica Analytical Guard Module, 8 μ , 4.6 × 50 mm, reference No. 83-101-G (Rainin Instrument Company, Mack Road, Box 4026, Woburn, MA 01888-4026), eluting with a mixture of dichloromethane and 2-propyl alcohol (96: 4 , Volume / volume), flow rate 0.5 ml / minute, UV detection at 254 nm). ¹ H NMR [400 MHz, (CD ₃ ) ₂ SO, 383 ° K]: δ 0.96 (s, 3H); 1.04 (s, 3H); 1.30 (m, 1H); 1.47 (m, 1H); 1.70 to 2.05 (m, 5H); 2.29 (s, 3H); 3.55 to 3.65 (m, 3H); 3.61 (s, 2H); 3.74 (d, J = 14.5Hz, 1H); 3.75 to 3.95 (m, 3H); 3.91 (s, 3H); 4.00 (m, 1H); 4.10 (m, 1H); 6.89 (dd, J = 8 and 2Hz, 1H); 7.00 (bt, J = 8Hz, 1H); 7.04 (d, J = 1.5Hz, 1H); 7.10 to 7.25 (m, 2H); 7.22 (d, J = 8.5Hz, 1H); 7.40 to 7.60 (m, 7H); 7.70 (bd, J = 8Hz, 1H); 8.01 (d, J = 8Hz, 1H); 8.17 (bs, 1H); 8.23 (bs, 1H); 9.57 (bs, 1H). MS (LSIMS): 804 [M + H] ⁺ .
• (ii) N- {4- [1-Benzoyl-4- (10,10-dimethyl-3,3-dioxo-3,6-thia-4-aza-tricyclo [5.2.1.0.1.5] decane-4 carbonyl) -pyrrolidin-3-yl] -phenyl} -2- [3-methoxy-4- (3-o-tolyl-ureido) -phenyl] -acetamide (diastereoisomer B), (0.187 g). HPLC: R _T = 8.32 minutes. ¹ H-NMR [400 MHz, (CD ₃ ) ₂ SO, 383 ° K]: δ 0.77 (s, 3H); 0.91 (s, 3H); 1.27 (m, 1H); 1.41 (m, 1H); 1.65 to 2.00 (m, 5H); 2.29 (s, 3H); 3.50 to 3.95 (m, 7H); 3.60 (s, 2H); 3.91 (s, 3H); 3.95 to 4.05 (m, 2H); 6.87 (dd, J = 8 and 2Hz, 1H); 6.99 (bt, J = 8Hz, 1H); 7.03 (d, J = 1.5Hz, 1H); 7.10 to 7.25 (m, 2H); 7.23 (d, J = 8.5Hz, 2H); 7.40 to 7.60 (m, 7H); 7.69 (bd, J = 8Hz, 1H); 8.00 (d, J = 8Hz, 1H); 8.18 (bs, 1H); 8.23 (bs, 1H); 9.58 (bs, 1H). MS (LSIMS): 804 [M + H] ⁺ .

IN VITRO AND IN VIVO TEST PROCEDURES

1. Inhibitory effects of compounds on VLA4-dependent cell adhesion Fibronectin and VCAM.

• 1.1 Metabolic Marking of RAMOS Cells. RAMOS cells (a pre-B cell line from ECACC, Porton Down, UK) are cultured in RPMI culture medium (Gibco, UK) supplemented with 5% fetal calf serum (FCS, Gibco, UK). Prior to the assay, cells are suspended at a concentration of 0.5 x 10 ⁶ cells / ml RPMI and labeled with 400 μCi / 100 ml [ ³ H] -methionine (Amersham, UK) for 18 hours at 37 ° C.
• 1.2 96-well plate preparation for adhesion assay. Cytostar plates (Amersham, UK) were coated with 50 μl / well of either 3 μg / ml human soluble VCAM-1 (R & D Systems Ltd., UK) or 28.8 μg / ml human tissue fibronectin (Sigma, UK) , To control non-specific binding, 50 μl of phosphate buffered saline was added to the wells. The plates were then allowed to dry in an incubator at 25 ° C overnight. The next day, the plates were blocked with 200 μl / well Pucks buffer (Gibco, UK) supplemented with 1% BSA (Sigma, UK). The plates were left at room temperature in the dark for 2 hours. The blocking buffer was then discarded and the plates dried by inverting the plates and blotting gently with a paper towel. 50 μl / well of 3.6% dimethylsulfoxide in Pucks buffer supplemented with 5 mM manganese chloride (to activate the integrin receptor Sigma, UK) and 0.2% BSA (Sigma, UK) was added to the appropriate control test and non-binding. given specific binding assay wells in the plate. 50 μl / well of test compounds at appropriate concentrations diluted in 3.6% dimethyl sulfoxide in Pucks buffer supplemented with 5 mM manganese chloride and 0.2% BSA were added to the test wells. Metabolically labeled cells were suspended at 4 x 10 ⁶ cells / ml in pucks buffer supplemented with manganese chloride and BSA as above. 50 μl / well of cells in 3.6% dimethylsulfoxide in pucks buffer and supplements were added to all plate wells. The same procedure is available for plates coated with either VCAM-1 or fibronectin and the data are determined for the compound inhibition of cell binding on both substrates.
• 1.3 Performance of Assay and Data Analysis. The plates containing the cells in control and test compound wells are incubated in the dark at room temperature for 1 hour. The plates are then counted on a Wallac Microbeta scintillation counter (Wallac, UK) and the captured data is processed in Microsoft Excel (Microsoft, US). The data are expressed as an IC _50, namely the concentration of inhibitor at which 50% control bandages take place. The percent binding is determined from the equation: {[(C TB -C NS ) - (C I -C NS )] / (C TB -C NS )} X 100 =% bind, wherein C _{TB represents} the counts that bind to fibronectin (or VCAM-1) -coated wells without the inhibitor present, C _{NS represents} the counts present in wells without substrate, and C _{I represents} the counts present in wells containing cell adhesion inhibitor. Linkage data from this invention are expressed as IC ₅₀ for the inhibition of cell adhesion to both fibronectin and VCAM-1. Certain compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC ₅₀ values in the range of 100 micromolar to 1 nanomolar. Preferred compounds of the invention inhibit cell adhesion to fibronectin and VCAM-1 with IC ₅₀ values in the range of 10 nanomolar to 1 nanomolar.

2. Inhibition of antigen-induced Airway inflammation in the mouse and rat

• 2.1 Sensitization of the animals. rats (Brown Norwegians, Harland Olac, GB) will be on days 0, 12 and 21 with ovalbumin (100 μg, intraperitoneal [i.p.], Sigma, UK) administered with aluminum hydroxide adjuvant (100 mg, i.p., Sigma, GB) in saline (1 ml, i.p.). In addition will be Mice (C57) on days 0 and 12 with ovalbumin (10 μg, i.p.) administered with aluminum hydroxide adjuvant (20 mg, i.p.) in saline (0.2 ml, i.p.), sensitized.
• 2.2 Antigenic irritation. Rats are irritated every day between days 28-38, while mice are irritated every day between days 20-30. The animals are challenged by exposure for 30 minutes (rats) or 1 hour (mice) to an aerosol of ovalbumin (10 g / L) generated by ultrasound distribution (deVilbiss Ultraneb, US) and directed into an exposure chamber.
• 2.3 Treatment protocols. Animals become as required treated before and after antigen challenge. The inventive, in Water soluble Compounds are dissolved in water (for oral, p.o. dosage) or saline solution (for intratracheal, i.t. dosage). Insoluble compounds are used as suspensions by grinding and ultrasonication of the Solid in 0.5% methyl cellulose / 0.2% polysorbate-80 in water (for p.o. dosing, both Merck GB Ltd., GB) or saline solution (for i.t. dosing). Dose volumes are: for Rats 1 ml / kg, p.o. or 0.5 mg / kg, i.t .; for mice 10 ml / kg, p.o. or 1 ml / kg, i.t.
• 2.4 Assessment of airway inflammation. Cell accumulation in the lungs will be 24 hours after irritation (rats) or 48-72 hours after irritation (mice) rated. The animals are treated with sodium pentabarbitone (200 mg / kg, i.p., Pasteur Merieux, France) and the trachea is cannulated immediately. Cells are removed from the airway lumen by bronchoalveolar lavage (BAL) and from the lung tissue by enzymatic (collagenase, Sigma, GB) Disaggregation as obtained below. BAL is going through do the washing up airways with 2 aliquots (10 ml / kg each) RPMI 1640 Medium (Gibco, UK) containing 10% fetal calf serum (FCS, Serotec Ltd., UK). The removed BAL aliquots are pooled and cell counting became as described below. Immediately after BAL rinses lung vasculature with RPMI 1640 / FCS to remove the blood pool the cells. The lungs are removed and placed in 0.5 mm pieces cut. Samples (rats: 400 mg, mice: 150 mg) of homogeneous Pulmonary tissues are treated with RPMI 1640 / FCS with collagenase (20 U / ml for 2 hours, then 60 U / ml for 1 hour, 37 ° C) to disaggregate cells of the tissue incubated. Won cells are washed in RPMI 1640 / FCS. The counts of total leukocytes, derived from the airway lumen and lung tissue, are performed with an automated cell counter (Cobas Argos, US). Various counts of eosinophils, neutrophils and mononuclear cells are due Light microscopy of cytoplasmic compound preparations, stained with Wright Giemza staining (Sigma, UK). T cells are analyzed by flow cytometry (EPICS XL, Coulter Electronics, US) using fluorophore-labeled antibodies against CD2 (a ladle T cell marker, used to quantitate total T cells), CD4, CD8 and CD25- (a marker for activated T cells). All antibodies were supplied by Serotec Ltd., UK.
• 2.5 Data Analysis. Cell data were taken as mean cell numbers of non-irritated, irritated and carrier-treated, and irritated and compound-treated groups, including the standard error of the Average, expressed. Statistical analysis of the difference among the treated groups was using a one-way analysis of a variance over the Mann-Whitney test rated. If p <0.05, There was no statistical significance.

Claims (49)

Compound of the formula (I):

wherein: one of A ¹ , A ² and A ^{3 represents} NR ² and the other C represents (R ³ ) (R ⁴ ); R ¹ R ^{5 is} Z ¹ -Het or R ⁶ N (R ⁷ ) -C (= O) -NH-Ar ² -; R ^{2 represents} -C (= O) -R ⁸ , -C (= O) -OR ^8a or R ^8b ; R ³ and R ⁴ each represent hydrogen or R ⁸ ; R ⁵ aryl; heteroaryl; Alkyl, alkenyl or alkynyl, each optionally substituted with R ⁹ , -Z ² R ¹⁰ , -Z ³ H, -C (= O) -R ¹⁰ , -NR ¹¹ -C (= Z ³ ) -R ¹¹ , -NR ¹¹ -C (= O) -OR ¹⁰ , -NR ¹¹ -SO ₂ -R ¹⁰ , -SO ₂ -NY ¹ Y ² , -NY ¹ Y ² or -C (= Z ³ ) -NY ¹ Y ² ; or cycloalkyl, or heterocycloalkyl, each optionally substituted with R ¹⁰ , -Z ² R ¹⁰ , -Z ³ H, -C (= O) -R ¹⁰ , -NR ¹¹ -C (= Z ³ ) -R ¹⁰ , -NR ¹¹ -C (= O) -OR ¹⁰ , -NR ¹¹ -SO ₂ -R ¹⁰ , -SO ₂ -NY ¹ Y ² , -NY ¹ Y ² or -C (= Z ³ ) -NY ¹ Y ² ; R ^{6 represents} hydrogen or C ₁ -C ₄ -alkyl and R ^{7 represents} aryl, arylalkyl, heteroaryl or heteroarylalkyl; or R ⁶ and R ⁷ together with the nitrogen atom to which they are attached form a cyclic amine; R ^{8 is} alkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl or alkyl substituted with an acidic functional group or a corresponding protected derivative, or with -Z ³ H, -Z ² R ¹⁰ , -C ( = O) -NY ¹ Y ² or -NY ¹ Y ² , represents; R ^{8a represents} alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl; R ^{8b represents} alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or alkyl substituted with an acidic functional group or a corresponding protected derivative; R ^{9 represents} aryl, cycloalkyl, cycloalkenyl, heteroaryl or heterocycloalkyl; R ^{10 represents} alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heterocycloalkyl or heterocycloalkylalkyl; R ^{11 represents} hydrogen or lower alkyl; R ^{12 represents} a direct bond or an alkylene chain, an alkenylene chain, or an alkynylene chain; R ^{13 is} a direct bond, cycloalkylene, heterocycloalkylene; Aryldiyl, heteroaryldiyl, -C (= Z ³ ) -NR ¹¹ -, -NR ¹¹ - C (= Z ³ ) -, -Z ³ -, -C (= O) -, -C (= NOR ¹¹ ) -, -NR ¹¹ -, -NR ¹¹ -C (= Z ³ ) -NR ¹¹ -, -SO ₂ -NR ¹¹ -, -NR ¹¹ -SO ₂ -, -OC (= O) -, -C (= O) -O-, -NR ¹¹ -C (= O) -O- or -OC (= O) -NR ¹¹ -; Ar ^{1 represents} aryldiyl or heteroaryldiyl; Ar ^{2 represents} aryldiyl or heteroaryldiyl; Het is a saturated, partially saturated or fully unsaturated 8 to 10 membered bicyclic ring system which represents at least one heteroatom selected from O, S or N, optionally substituted with one or more aryl group substituents; L ^{1 represents} an -R ¹² -R ¹³ bond; Y carboxy or an acidic bioisosteres selected from the group consisting of -C (= O) -NHOH, -C (= O) -CH ₂ OH, -C (= O) -CH ₂ SH, -C (= O ) -NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonylcarbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3-hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1,2,4-oxadiazolidinyl, 3-hydroxyisoxazolyl and 3-hydroxy-1-methylpyrazolyl; Y ¹ and Y ^{2 are} independently hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY ¹ Y ² may form a cyclic amine; Z ^{1 represents} NH; Z ^{2 represents} O or S (O) _n ; Z ^{3 represents} O or S; n is zero or an integer 1 or 2; (but only compounds in which an oxygen, nitrogen or sulfur atom is bonded directly to the carbon-carbon multiple bond of an alkenyl or alkynyl radical); and their ester prodrugs and pharmaceutically acceptable salts and solvates of such compounds and their ester prodrugs. A compound according to claim 1 wherein R ^{1 represents} R ⁶ N (R ⁷ ) -C (= O) -NH-Ar ² -. A compound according to claim 2, wherein R ^{7 represents} an optionally substituted phenyl. A compound according to claim 2 or claim 3 wherein R ^{6 is} hydrogen. A compound according to claim 2 wherein R ^{6 is} hydrogen and R ^{7 is} phenyl or ortho substituted phenyl. A compound according to claim 5 wherein R ^{7 is} phenyl substituted in the ring ortho position with C _1-4 alkyl. A compound according to any one of claims 2 to 6, wherein Ar ^{2 is} optionally substituted phenylene. A compound according to claim 7, wherein Ar ^{2 is} phenylene substituted with C _1-4 alkyl or C _1-4 alkoxy. A compound according to claim 7 wherein Ar ^{2 is} optionally substituted p-phenylene. A compound according to claim 8 wherein Ar ^{2 is} p-phenylene substituted at the 3-position with C _1-4 -alkyl or C _1-4 -alkoxy. A compound according to claim 1, wherein R ^{1 represents} R ⁵ Z ¹ -Het-. A compound according to claim 11 wherein Het is an optionally substituted 8 to 10 membered bicyclic system

arstell, in which ring

represents a 5- or 6-membered heteroaryl ring, ring

represents a 5- or 6-membered heteroaryl ring or a benzene ring and the two rings are linked together by a carbon-carbon bond or a carbon-nitrogen bond, Z ^{1 represents} NH and R ^{5 represents} optionally substituted aryl. A compound according to claim 12 wherein Het is an optionally substituted 9-membered bicyclic system

represents, wherein ring

represents a 5-membered azaheteroaryl ring

represents a benzene ring and the two rings are linked together by a carbon-carbon bond. A compound according to claim 13 wherein Het is optionally substituted benzoxazolyl or optionally substituted benzimidazolyl represents. A compound according to claim 14 wherein Het is benzoxazolyl or benzimidazolyl, each optionally substituted on the benzene ring with one or more groups selected from C _1-4 alkyl, C _1-4 alkoxy, amino, halogen, hydroxy, C _1-4 Alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, nitro or trifluoromethyl. A compound according to any preceding claim, wherein L ^{1 represents} a -R ¹² -R ¹³ -bond wherein R ^{12 represents} a straight or branched C _1-4 alkylene chain and R ^{13 represents} -C (= O) -NH-. A compound according to claim 16, wherein R ^{12 represents} methylene. A compound according to any preceding claim, wherein Ar ^{1 represents} optionally substituted p-phenylene. A compound according to claim 18, wherein Ar ^{1 represents} unsubstituted p-phenylene. A compound according to any preceding claim wherein one of A ¹ , A ² and A ^{3 represents} NR ² and represents the other CH ₂ . A compound according to claim 20, wherein R ^{2 represents} - (C = O) -R ⁸ , wherein R ^{8 is} as defined in claim 1. A compound according to claim 21 wherein R ^{8 is} C _1-4 alkyl or phenyl. A compound according to claim 20 wherein R ^{2 is} arylC _1-4 alkyl. A compound according to claim 23, wherein R ^{2 is} benzyl. A compound according to any preceding claim, wherein Y represents carboxy. A compound according to claim 1, which has the formula (Ia):

wherein A ¹ , A ² , A ³ , R ¹² , Ar ¹ and Y are as defined in a relevant preceding claim; R ^{15 represents} hydrogen, halogen, C _1-4 alkyl or C _1-4 alkoxy, X ^{1 represents} CR ¹⁶ (wherein R ^{16 represents} hydrogen, C _1-4 alkyl or C _1-4 alkoxy); X ² and X ^{3 are} independently N or CR ¹⁷ (wherein R ^{17 is} hydrogen, amino, halo, hydroxy, C _1-4 alkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylsulfinyl, C _1-4 alkylsulfonyl, nitro or trifluoromethyl) and the R ¹² -containing group is attached to the ring in the 3- or 4-position and their ester prodrugs and pharmaceutically acceptable salts and solvates of compounds of formula (Ia) and their ester prodrugs , A compound according to claim 26, wherein R ^{15 is} hydrogen; X ^{1 represents} CR ¹⁶ (wherein R ^{16 represents} C _1-4 alkyl); X ^{2 represents} CR ¹⁷ (wherein R ^{17 represents} C _1-4 alkoxy); X ^{3 represents} CH; R ^{12 represents} a straight C _1-4 alkylene chain; Ar ^{1 represents} p-phenylene; Y represents carboxy and the group containing R ¹² is attached to the ring in the 4-position. A compound according to claim 26 or claim 27 wherein one of A ¹ , A ² and A ^{3 represents} NR ² and represents the other CH ₂ . A compound according to claim 28, wherein R ^{2 is} -C (= O) R ⁸ , wherein R ^{8 is} as defined in claim 1. A compound according to claim 29 wherein R ^{8 is} C _1-4 alkyl or phenyl. A compound according to claim 28 wherein R ^{2 is} arylC _1-4 alkyl. A compound according to claim 31, wherein R ^{2 is} benzyl. A compound according to claim 1 which has the formula (Id):

wherein R ⁵ , R ¹² , Ar ¹ , A ¹ , A ² , A ³ and Y are as defined in a relevant preceding claim; X NR or O (wherein R is H or C _1-4 alkyl); R ^{19 is} hydrogen, C _1-4 -alkyl or C _1-4 -alkoxy and their ester prodrugs; and pharmaceutically acceptable salts and solvates of compounds of formula (Id) and their ester prodrugs. A compound according to claim 33, wherein R ^{5 is} optionally substituted phenyl; X represents O; R ^{12 represents} a straight C _1-4 alkylene chain; Ar ^{1 represents} p-phenylene; Y represents carboxy and the group containing R ¹² is bonded to the benzoxazole ring in the 6-position. A compound according to claim 33 or claim 34, wherein one of A ¹ , A ² and A ^{3 represents} NR ² and represents the other CH ₂ . A compound according to claim 35 wherein R ^{2 is} -C (= O) -R ⁸ wherein R ^{8 is} as defined in claim 1. A compound according to claim 36 wherein R ^{8 is} C _1-4 alkyl or phenyl. A compound according to claim 35, wherein R ^{2 is} arylC _1-4 alkyl. A compound according to claim 38, wherein R ^{2 is} benzyl. A pharmaceutical composition comprising a effective amount of a compound according to claim 1 or a corresponding one N-oxide, or an ester prodrug thereof, or a pharmaceutically acceptable one Salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, in association with a pharmaceutical acceptable carrier or excipients. A compound according to claim 1 or a corresponding N-oxide, or one Ester prodrug thereof, or a pharmaceutically acceptable Salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, for use in therapy. A compound according to claim 1 or a corresponding N-oxide, or one Ester prodrug thereof, or a pharmaceutically acceptable Salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, for use in the treatment of a Patient under conditions, those mediated by the administration of an inhibitor of α4β1 Cell adhesion can be alleviated suffers or for it is vulnerable. A composition according to claim 40 for use in the treatment of a patient suffering from conditions that alleviated by the administration of an inhibitor of α4β1 mediated cell adhesion can be suffers or for it susceptible is. A compound or composition according to claim 1 or 40 for use in the treatment of inflammatory Diseases. A compound or composition according to claim 1 or 40 for use in the treatment of asthma. Use of a compound according to claim 1 or a corresponding N-oxide, or ester prodrug thereof, or a pharmaceutically acceptable Salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, in the manufacture of a medicament for the Treatment of a patient suffering from conditions caused by the administration an inhibitor of α4β1 mediated Cell adhesion can be alleviated suffers or for it susceptible is. Use of a compound according to claim 1 or a corresponding N-oxide, or ester prodrug thereof, or a pharmaceutically acceptable Salt or solvate of such a compound or its N-oxide or an ester prodrug thereof, in the manufacture of a medicament for the Treatment of asthma. Intermediates of the formula (II)

wherein R ¹¹ , Ar ¹ , A ¹ , A ² and A ^{3 are} as defined in claim 1 and R ^{20 is} alkyl, alkenyl or arylalkyl and of the formula (1)

wherein Ar ¹ , A ¹ , A ² and A ^{3 are} as defined in claim 1 and R ^{20 represents} alkyl, alkenyl or arylalkyl. Compounds of the formula (IV)

wherein R ¹ , L ¹ and Ar ^{1 are} as hereinbefore defined, Y is carboxy and one of A ¹ , A ² and A ^{3 is} NH and the other C (R ³ ) represents (R ⁴ ).